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CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis

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    4 These authors share first authorship.
    Elien Van Nuffel
    Footnotes
    4 These authors share first authorship.
    Affiliations
    Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, Ghent University–VIB, Ghent, Belgium

    Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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  • Author Footnotes
    4 These authors share first authorship.
    Anja Schmitt
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    4 These authors share first authorship.
    Affiliations
    Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Tuebingen, Germany
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  • Inna S. Afonina
    Affiliations
    Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, Ghent University–VIB, Ghent, Belgium

    Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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  • Klaus Schulze-Osthoff
    Affiliations
    Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Tuebingen, Germany
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    5 These authors share senior authorship.
    Rudi Beyaert
    Correspondence
    Rudi Beyaert, Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, Ghent University–VIB, Technologiepark 927, Ghent 9052, Belgium.
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    5 These authors share senior authorship.
    Affiliations
    Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, Ghent University–VIB, Ghent, Belgium

    Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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    5 These authors share senior authorship.
    Stephan Hailfinger
    Correspondence
    Correspondence: Stephan Hailfinger, Interfaculty Institute for Biochemistry, University of Tuebingen, Hoppe-Seyler-Str. 4, Tuebingen 72076, Germany.
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    5 These authors share senior authorship.
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    Interfaculty Institute for Biochemistry, Eberhard Karls University of Tuebingen, Tuebingen, Germany
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  • Author Footnotes
    4 These authors share first authorship.
    5 These authors share senior authorship.
Open ArchivePublished:December 08, 2016DOI:https://doi.org/10.1016/j.jid.2016.09.031
      Mutations in caspase recruitment domain-containing protein 14 (CARD14) have been linked to susceptibility to psoriasis. CARD14 is an intracellular scaffold protein that regulates proinflammatory gene expression. Recent studies have offered novel insights into the mechanisms of CARD14-mediated signaling in keratinocytes and the molecular impact of psoriasis-associated CARD14 mutations. CARD14 forms a signaling complex with BCL10 and the paracaspase MALT1, and this process is enhanced upon pathogenic CARD14 mutation, culminating in the activation of MALT1 protease activity and psoriasis-associated gene expression. This review summarizes the current knowledge of CARD14/MALT1-mediated signaling in keratinocytes and its therapeutic implications in psoriasis.

      Abbreviations:

      BCL10 (B-cell lymphoma/leukemia 10), CARD14 (caspase recruitment domain-containing protein 14), CARMA (CARD-containing MAGUK protein), CC (coiled coil), MAGUK (membrane-associated guanylate kinase), MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), PKC (protein kinase C), TNF (tumor necrosis factor)

      Psoriasis, a Skin Disease With a Strong Genetic Component

      Psoriasis is a common chronic autoinflammatory skin disease that affects 2–3% of the world's population and greatly impairs the quality of life of affected individuals. Psoriasis vulgaris, the most prevalent disease type, is characterized by well-demarcated red, scaly plaques. More rare types of psoriasis also exist, such as pustular, palmoplantar, inverse, erythrodermic, and guttate psoriasis (
      • Deng Y.
      • Chang C.
      • Lu Q.
      The inflammatory response in psoriasis: a comprehensive review.
      ,
      • Lowes M.A.
      • Suarez-Farinas M.
      • Krueger J.G.
      Immunology of psoriasis.
      ,
      • Nestle F.O.
      • Kaplan D.H.
      • Barker J.
      ). Furthermore, psoriasis is associated with several comorbidities, and almost 30% of patients suffer from psoriatic arthritis, indicating that this disease is not only restricted to the skin (
      • Mease P.J.
      • Gladman D.D.
      • Papp K.A.
      • Khraishi M.M.
      • Thaci D.
      • Behrens F.
      • et al.
      Prevalence of rheumatologist-diagnosed psoriatic arthritis in patients with psoriasis in European/North American dermatology clinics.
      ).
      Psoriasis-affected skin is characterized by a thickened epidermis with scaly patches, due to excessive proliferation and aberrant differentiation of keratinocytes, as well as redness caused by increased dilatation of the dermal blood vessels and infiltration of immune cells (
      • Lowes M.A.
      • Suarez-Farinas M.
      • Krueger J.G.
      Immunology of psoriasis.
      ). Although the pathogenesis of psoriasis has not yet been completely elucidated, it is generally believed to arise from a complex interplay between hyperproliferating keratinocytes and infiltrating, activated immune cells, mainly dendritic cells and T cells. Skin injury or associated infections trigger keratinocytes to elicit IL-23 and IL-12 production in dendritic cells. These cytokines in turn activate T cells and induce the production of several psoriatic cytokines, such as IL-17, IFN-γ, tumor necrosis factor (TNF), and IL-22, which further induce keratinocyte hyperproliferation as well as the production of chemokines to sustain the recruitment and activation of immune cells (
      • Lowes M.A.
      • Suarez-Farinas M.
      • Krueger J.G.
      Immunology of psoriasis.
      ).
      Even though the etiology of psoriasis is still largely unknown, the concordance rate of psoriasis in monozygotic twins of approximately 70% illustrates that there is a strong genetic component. Through linkage disequilibrium studies in psoriasis-affected families, multiple psoriasis susceptibility (PSORS) loci have been identified (
      • Lowes M.A.
      • Suarez-Farinas M.
      • Krueger J.G.
      Immunology of psoriasis.
      ). However, most of the genes responsible for the observed susceptibility are not known (
      • Harden J.L.
      • Krueger J.G.
      • Bowcock A.M.
      The immunogenetics of psoriasis: a comprehensive review.
      ,
      • Lowes M.A.
      • Suarez-Farinas M.
      • Krueger J.G.
      Immunology of psoriasis.
      ). Recently, mutations in caspase recruitment domain-containing protein 14 (CARD14), a gene located in the PSORS2 locus, have been linked to psoriasis susceptibility (
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      ). Here, we review the role of CARD14-mediated signaling in keratinocytes and its potential implications for psoriasis therapy.

      CARD14 structure and function

      CARD14, also known as CARD-containing MAGUK protein 2 (CARMA2) and Bimp2, is a member of the CARMA family of proteins, which also includes CARD11/CARMA1 and CARD10/CARMA3 (
      • Bertin J.
      • Wang L.
      • Guo Y.
      • Jacobson M.D.
      • Poyet J.L.
      • Srinivasula S.M.
      • et al.
      CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B.
      ,
      • Gaide O.
      • Martinon F.
      • Micheau O.
      • Bonnet D.
      • Thome M.
      • Tschopp J.
      Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation.
      ,
      • McAllister-Lucas L.M.
      • Inohara N.
      • Lucas P.C.
      • Ruland J.
      • Benito A.
      • Li Q.
      • et al.
      Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-kappaB induction.
      ,
      • Scudiero I.
      • Vito P.
      • Stilo R.
      The three CARMA sisters: so different, so similar: a portrait of the three CARMA proteins and their involvement in human disorders.
      ). Similar to CARD10 and CARD11, CARD14 acts as a scaffolding protein that can activate the inflammatory transcription factor NF-κB (
      • Bertin J.
      • Wang L.
      • Guo Y.
      • Jacobson M.D.
      • Poyet J.L.
      • Srinivasula S.M.
      • et al.
      CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B.
      ). The CARMA proteins have a uniform domain structure consisting of an N-terminal CARD domain followed by a coiled-coil (CC) domain, a linker region, and a C-terminal membrane-associated guanylate kinase domain (MAGUK) comprising PDZ, SH3, and GUK subdomains (Figure 1) (
      • Bertin J.
      • Wang L.
      • Guo Y.
      • Jacobson M.D.
      • Poyet J.L.
      • Srinivasula S.M.
      • et al.
      CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B.
      ,
      • Gaide O.
      • Martinon F.
      • Micheau O.
      • Bonnet D.
      • Thome M.
      • Tschopp J.
      Carma1, a CARD-containing binding partner of Bcl10, induces Bcl10 phosphorylation and NF-kappaB activation.
      ,
      • McAllister-Lucas L.M.
      • Inohara N.
      • Lucas P.C.
      • Ruland J.
      • Benito A.
      • Li Q.
      • et al.
      Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-kappaB induction.
      ). Whereas the CARD and CC domains are necessary for NF-κB activation and self-oligomerization, the linker region might exert an autoinhibitory function (
      • Bertin J.
      • Wang L.
      • Guo Y.
      • Jacobson M.D.
      • Poyet J.L.
      • Srinivasula S.M.
      • et al.
      CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B.
      ,
      • Howes A.
      • O'Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ,
      • Matsumoto R.
      • Wang D.
      • Blonska M.
      • Li H.
      • Kobayashi M.
      • Pappu B.
      • et al.
      Phosphorylation of CARMA1 plays a critical role in T cell receptor-mediated NF-kappaB activation.
      ,
      • Sommer K.
      • Guo B.
      • Pomerantz J.L.
      • Bandaranayake A.D.
      • Moreno-Garcia M.E.
      • Ovechkina Y.L.
      • et al.
      Phosphorylation of the CARMA1 linker controls NF-kappaB activation.
      ,
      • Tanner M.J.
      • Hanel W.
      • Gaffen S.L.
      • Lin X.
      CARMA1 coiled-coil domain is involved in the oligomerization and subcellular localization of CARMA1 and is required for T cell receptor-induced NF-kappaB activation.
      ). The MAGUK domain targets proteins to the membrane and is involved in various processes, such as signal transduction, tight junction formation, cell proliferation, apoptosis, and differentiation (
      • te Velthuis A.J.
      • Admiraal J.F.
      • Bagowski C.P.
      Molecular evolution of the MAGUK family in metazoan genomes.
      ). However, its specific role in CARD14-mediated signaling is still unclear.
      Figure 1
      Figure 1Comparison of CBM complex formation in T cells and keratinocytes. Triggering of the ITAM-containing receptors TCR and dectin-1 activates kinases from the Src and PKC families, which are believed to be required for the assembly of a CARD-BCL10-MALT1 (CBM) signaling complex. Whereas BCL10 and MALT1 are recruited to CARD11 in lymphocytes, a CARD14-containing complex is formed in keratinocytes. Both CARD11 and CARD14 interact with BCL10 via their CARD domains, which is only accessible in CARD11 after PKC-mediated phosphorylation of its linker region. The CBM complex subsequently activates the transcription factor NF-κB in two ways. First, it acts as a scaffold to recruit and activate the IKK complex, which phosphorylates and thus targets IκBα for proteasomal degradation, allowing the nuclear translocation of NF-κB. Secondly, it promotes optimal NF-κB activation by MALT1-mediated cleavage of RelB and A20. In both T cells and keratinocytes, NF-κB regulates the expression of proinflammatory cytokines. BCL10, B-cell lymphoma/leukemia 10; CARD14, caspase recruitment domain-containing protein 14; CBM, CARD-BCL10-MALT1; CC, coiled coil; ITAM, immunoreceptor tyrosine-based activation motif; IκB, inhibitor of κB; IKK, IκB kinase; MAGUK, membrane-associated guanylate kinase; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; PKC, protein kinase C; TCR, T cell receptor.
      The CARD14 gene gives rise to several splice variants. In addition to the full-length form (CARD14fl), a shorter splice variant (CARD14sh), which lacks a part of the membrane-associated guanylate kinase domain, has been described (
      • Scudiero I.
      • Zotti T.
      • Ferravante A.
      • Vessichelli M.
      • Vito P.
      • Stilo R.
      Alternative splicing of CARMA2/CARD14 transcripts generates protein variants with differential effect on NF-kappaB activation and endoplasmic reticulum stress-induced cell death.
      ). The functional differences between CARD14fl and CARD14sh have remained elusive thus far, as they seem equally potent in mounting an NF-κB response (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ). A third splice variant, CARD14cardless, lacks the CARD domain as well as part of the CC domain and the SH3 and GUK domains. Because of the missing CARD domain, CARD14cardless is not able to activate NF-κB and may function as a dominant-negative regulator of CARD14 signaling (
      • Scudiero I.
      • Zotti T.
      • Ferravante A.
      • Vessichelli M.
      • Vito P.
      • Stilo R.
      Alternative splicing of CARMA2/CARD14 transcripts generates protein variants with differential effect on NF-kappaB activation and endoplasmic reticulum stress-induced cell death.
      ).
      The three CARD14 splice variants are predominantly expressed in placenta and skin tissue (
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      ). In healthy skin, CARD14 is primarily expressed in the keratinocytes of the basal layer of the epidermis. In contrast, psoriatic skin lesions show increased levels of CARD14 in the upper layers of the epidermis and reduced CARD14 levels in the basal layer (
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      ). This expression pattern might reflect the deregulated differentiation of keratinocytes in psoriasis-affected skin and could suggest a role for CARD14 in keratinocyte differentiation.
      • Harden J.L.
      • Lewis S.M.
      • Pierson K.C.
      • Suarez-Farinas M.
      • Lentini T.
      • Ortenzio F.S.
      • et al.
      CARD14 expression in dermal endothelial cells in psoriasis.
      also showed that CARD14 expressed in dermal endothelial cells could modulate the expression of chemokines such as CXCL8, CXCL10, and CCL2, which sensitize the skin vasculature of psoriasis patients bearing CARD14 mutations to inflammation. Because psoriasis is often associated with cardiovascular comorbidities, these observations might also imply a role for CARD14 in cardiovascular disease (
      • Yim K.M.
      • Armstrong A.W.
      Updates on cardiovascular comorbidities associated with psoriatic diseases: epidemiology and mechanisms.
      ).

      CARD14 variants in psoriasis

      In 2012, Jordan et al. described several common and rare variants of CARD14 that are directly associated with psoriasis in familial and nonfamilial cases (
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ). Since then, several studies have reported associations of CARD14 variants with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis, and palmoplantar pustular psoriasis (
      • Ammar M.
      • Bouchlaka-Souissi C.
      • Helms C.A.
      • Zaraa I.
      • Jordan C.T.
      • Anbunathan H.
      • et al.
      Genome-wide linkage scan for psoriasis susceptibility loci in multiplex Tunisian families.
      ,
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      ,
      • Eskin-Schwartz M.
      • Basel-Vanagaite L.
      • David M.
      • Lagovsky I.
      • Ben-Amitai D.
      • Smirin-Yosef P.
      • et al.
      Intra-familial variation in clinical phenotype of CARD14-related psoriasis.
      ,
      • Feng C.
      • Wang T.
      • Li S.J.
      • Fan Y.M.
      • Shi G.
      • Zhu K.J.
      CARD14 gene polymorphism c.C2458T (p.Arg820Trp) is associated with clinical features of psoriasis vulgaris in a Chinese cohort.
      ,
      • Gonzalez-Lara L.
      • Coto-Segura P.
      • Penedo A.
      • Eiris N.
      • Diaz M.
      • Santos-Juanes J.
      • et al.
      SNP rs11652075 in the CARD14 gene as a risk factor for psoriasis (PSORS2) in a Spanish cohort.
      ,
      • Inoue N.
      • Dainichi T.
      • Fujisawa A.
      • Nakano H.
      • Sawamura D.
      • Kabashima K.
      CARD14 Glu138 mutation in familial pityriasis rubra pilaris does not warrant differentiation from familial psoriasis.
      ,
      • Korber A.
      • Mossner R.
      • Renner R.
      • Sticht H.
      • Wilsmann-Theis D.
      • Schulz P.
      • et al.
      Mutations in IL36RN in patients with generalized pustular psoriasis.
      ,
      • Mossner R.
      • Frambach Y.
      • Wilsmann-Theis D.
      • Lohr S.
      • Jacobi A.
      • Weyergraf A.
      • et al.
      Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-of-function mutations in IL36RN in European patients.
      ,
      • Qin P.
      • Zhang Q.
      • Chen M.
      • Fu X.
      • Wang C.
      • Wang Z.
      • et al.
      Variant analysis of CARD14 in a Chinese Han population with psoriasis vulgaris and generalized pustular psoriasis.
      ,
      • Sugiura K.
      • Muto M.
      • Akiyama M.
      CARD14 c.526G>C (p.Asp176His) is a significant risk factor for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort.
      ,
      • Sugiura K.
      • Kitoh T.
      • Watanabe D.
      • Muto M.
      • Akiyama M.
      Childhood-onset PsA in Down syndrome with psoriasis susceptibility variant CARD14 rs11652075.
      ,
      • Zhu K.
      • Shi G.
      • Liu H.
      • Zhu C.
      • Fan Y.
      Variants of CARD14 gene and psoriasis vulgaris in southern Chinese cohort.
      ). Furthermore, CARD14 variants have also been associated with pityriasis rubra pilaris, a distinct inflammatory skin disease characterized by keratotic follicular papules and salmon-colored erythematous plaques (
      • Eytan O.
      • Sarig O.
      • Sprecher E.
      • van Steensel M.A.
      Clinical response to ustekinumab in familial pityriasis rubra pilaris caused by a novel mutation in CARD14.
      ,
      • Fuchs-Telem D.
      • Sarig O.
      • van Steensel M.A.
      • Isakov O.
      • Israeli S.
      • Nousbeck J.
      • et al.
      Familial pityriasis rubra pilaris is caused by mutations in CARD14.
      ,
      • Has C.
      • Schwieger-Briel A.
      • Schlipf N.
      • Hausser I.
      • Chmel N.
      • Rosler B.
      • et al.
      Target-sequence capture and high throughput sequencing identify a de novo CARD14 mutation in an infant with erythrodermic pityriasis rubra pilaris.
      ,
      • Inoue N.
      • Dainichi T.
      • Fujisawa A.
      • Nakano H.
      • Sawamura D.
      • Kabashima K.
      CARD14 Glu138 mutation in familial pityriasis rubra pilaris does not warrant differentiation from familial psoriasis.
      ,
      • Li Q.
      • Jin Chung H.
      • Ross N.
      • Keller M.
      • Andrews J.
      • Kingman J.
      • et al.
      Analysis of CARD14 polymorphisms in pityriasis rubra pilaris: activation of NF-kappaB.
      ). An overview of all CARD14 variants identified in patients with psoriasis and pityriasis rubra pilaris is listed in Table 1.
      Table 1Overview of CARD14 variants associated with psoriasis or pityriasis rubra pilaris
      MutationExonDomainDiseaseEffect on NF-κB
      Fold change compared with unstimulated CARD14 WT.
      Reference
      p.Arg38Cys2CARDPsV0.11(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Arg62Gln2CARDPsV1.06(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Arg69Trp2CARDPsV/PsA0.144(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      )
      p.Gly117Ser3Between CARD and CCPsV/PsA/GPP3.71(
      • Ammar M.
      • Bouchlaka-Souissi C.
      • Helms C.A.
      • Zaraa I.
      • Jordan C.T.
      • Anbunathan H.
      • et al.
      Genome-wide linkage scan for psoriasis susceptibility loci in multiplex Tunisian families.
      ,
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      ,
      • Eskin-Schwartz M.
      • Basel-Vanagaite L.
      • David M.
      • Lagovsky I.
      • Ben-Amitai D.
      • Smirin-Yosef P.
      • et al.
      Intra-familial variation in clinical phenotype of CARD14-related psoriasis.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      ,
      • Korber A.
      • Mossner R.
      • Renner R.
      • Sticht H.
      • Wilsmann-Theis D.
      • Schulz P.
      • et al.
      Mutations in IL36RN in patients with generalized pustular psoriasis.
      )
      c.349+5G>A3Between CARD and CCPsVND(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      )
      c.349+1G>A3Between CARD and CCPRP type VND(
      • Fuchs-Telem D.
      • Sarig O.
      • van Steensel M.A.
      • Isakov O.
      • Israeli S.
      • Nousbeck J.
      • et al.
      Familial pityriasis rubra pilaris is caused by mutations in CARD14.
      )
      p.Met119Val4Between CARD and CCGPPND(
      • Qin P.
      • Zhang Q.
      • Chen M.
      • Fu X.
      • Wang C.
      • Wang Z.
      • et al.
      Variant analysis of CARD14 in a Chinese Han population with psoriasis vulgaris and generalized pustular psoriasis.
      )
      p.Leu124Pro4Between CARD and CCPRPND(
      • Eytan O.
      • Sarig O.
      • Sprecher E.
      • van Steensel M.A.
      Clinical response to ustekinumab in familial pityriasis rubra pilaris caused by a novel mutation in CARD14.
      )
      p.Glu138Ala4CCGPP8.95(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      )
      p.Glu138Lys4CCPRP type VND(
      • Has C.
      • Schwieger-Briel A.
      • Schlipf N.
      • Hausser I.
      • Chmel N.
      • Rosler B.
      • et al.
      Target-sequence capture and high throughput sequencing identify a de novo CARD14 mutation in an infant with erythrodermic pityriasis rubra pilaris.
      ,
      • Inoue N.
      • Dainichi T.
      • Fujisawa A.
      • Nakano H.
      • Sawamura D.
      • Kabashima K.
      CARD14 Glu138 mutation in familial pityriasis rubra pilaris does not warrant differentiation from familial psoriasis.
      )
      p.Glu138del4CCPRP type VND(
      • Fuchs-Telem D.
      • Sarig O.
      • van Steensel M.A.
      • Isakov O.
      • Israeli S.
      • Nousbeck J.
      • et al.
      Familial pityriasis rubra pilaris is caused by mutations in CARD14.
      )
      p.Glu142Lys4CCPsV4.03(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Glu142Gly4CCPsV5.00(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Leu150Arg4CCPsV1.79(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Arg151Gln4CCPsV1.766(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      )
      p.Arg151Trp4CCPsV0.576(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      )
      p.Leu156Pro4CCPRP type VND(
      • Fuchs-Telem D.
      • Sarig O.
      • van Steensel M.A.
      • Isakov O.
      • Israeli S.
      • Nousbeck J.
      • et al.
      Familial pityriasis rubra pilaris is caused by mutations in CARD14.
      )
      p.Arg166His4CCGPPND(
      • Qin P.
      • Zhang Q.
      • Chen M.
      • Fu X.
      • Wang C.
      • Wang Z.
      • et al.
      Variant analysis of CARD14 in a Chinese Han population with psoriasis vulgaris and generalized pustular psoriasis.
      )
      p.His171Asn4CCPsV0.68(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Asp176His4CCPsV/GPP + PsV/PPP2.78(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Mossner R.
      • Frambach Y.
      • Wilsmann-Theis D.
      • Lohr S.
      • Jacobi A.
      • Weyergraf A.
      • et al.
      Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-of-function mutations in IL36RN in European patients.
      ,
      • Sugiura K.
      • Muto M.
      • Akiyama M.
      CARD14 c.526G>C (p.Asp176His) is a significant risk factor for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort.
      ,
      • Zhu K.
      • Shi G.
      • Liu H.
      • Zhu C.
      • Fan Y.
      Variants of CARD14 gene and psoriasis vulgaris in southern Chinese cohort.
      )
      p.Arg179His4CCPsV/PPP1.38(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Mossner R.
      • Frambach Y.
      • Wilsmann-Theis D.
      • Lohr S.
      • Jacobi A.
      • Weyergraf A.
      • et al.
      Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-of-function mutations in IL36RN in European patients.
      )
      p.Val191Leu4CCPsV1.02(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Glu197Lys4CCPPP/PsV/PsA1.667(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      ,
      • Mossner R.
      • Frambach Y.
      • Wilsmann-Theis D.
      • Lohr S.
      • Jacobi A.
      • Weyergraf A.
      • et al.
      Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-of-function mutations in IL36RN in European patients.
      )
      p.Ser200Asn4CCPsV/GPP/PPP0.67(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Korber A.
      • Mossner R.
      • Renner R.
      • Sticht H.
      • Wilsmann-Theis D.
      • Schulz P.
      • et al.
      Mutations in IL36RN in patients with generalized pustular psoriasis.
      ,
      • Mossner R.
      • Frambach Y.
      • Wilsmann-Theis D.
      • Lohr S.
      • Jacobi A.
      • Weyergraf A.
      • et al.
      Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-of-function mutations in IL36RN in European patients.
      )
      p.Leu209Pro4CCPsV0.785(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      )
      p.Ala216Thr4CCPsV0.575(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      ,
      • Qin P.
      • Zhang Q.
      • Chen M.
      • Fu X.
      • Wang C.
      • Wang Z.
      • et al.
      Variant analysis of CARD14 in a Chinese Han population with psoriasis vulgaris and generalized pustular psoriasis.
      ,
      • Zhu K.
      • Shi G.
      • Liu H.
      • Zhu C.
      • Fan Y.
      Variants of CARD14 gene and psoriasis vulgaris in southern Chinese cohort.
      )
      p.Asp285Gly6NonePsV1.14(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Met338Val7CCPsV0.914(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      )
      p.Thr420Ala9nonePsV0.663(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      )
      c.1356+5G>A9CCPsVND(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      )
      p.Thr591Met13PDZPsVND(
      • Qin P.
      • Zhang Q.
      • Chen M.
      • Fu X.
      • Wang C.
      • Wang Z.
      • et al.
      Variant analysis of CARD14 in a Chinese Han population with psoriasis vulgaris and generalized pustular psoriasis.
      )
      p.Ile593 Asn13PDZPsV1.30
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      p.Ser602Leu13PDZPsV/GPP/PPP1.196(
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      )
      p.Arg682Trp15SH3PsV/GPP0.95(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Qin P.
      • Zhang Q.
      • Chen M.
      • Fu X.
      • Wang C.
      • Wang Z.
      • et al.
      Variant analysis of CARD14 in a Chinese Han population with psoriasis vulgaris and generalized pustular psoriasis.
      )
      p.Gly714Ser15SH3PsV1.02(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      p.Arg820Trp18GUKPsV/PsAND(
      • Feng C.
      • Wang T.
      • Li S.J.
      • Fan Y.M.
      • Shi G.
      • Zhu K.J.
      CARD14 gene polymorphism c.C2458T (p.Arg820Trp) is associated with clinical features of psoriasis vulgaris in a Chinese cohort.
      ,
      • Gonzalez-Lara L.
      • Coto-Segura P.
      • Penedo A.
      • Eiris N.
      • Diaz M.
      • Santos-Juanes J.
      • et al.
      SNP rs11652075 in the CARD14 gene as a risk factor for psoriasis (PSORS2) in a Spanish cohort.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Sugiura K.
      • Kitoh T.
      • Watanabe D.
      • Muto M.
      • Akiyama M.
      Childhood-onset PsA in Down syndrome with psoriasis susceptibility variant CARD14 rs11652075.
      )
      p.Asp973Glu21GUKPsVND(
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      )
      Details on the location of the mutations, their disease occurrence, and their effect on NF-κB activation is shown. The exon sequence was determined using transcript CARD14-201 (ENST00000344227).
      Abbreviations: CARD, caspase recruitment domain; CC, coiled coil; GPP, generalized pustular psoriasis; GUK, guanylate kinase-like; ND, not determined; PDZ, postsynaptic density 95/disk large/zona occludens 1; PPP, palmoplantar pustular psoriasis; PsA, psoriatic arthritis; PsV, psoriasis vulgaris; PRP, pityriasis rubra pilaris; SH3, SRC homology 3.
      1 Fold change compared with unstimulated CARD14 WT.
      Most of the observed CARD14 missense variants are heterozygous. Interestingly, exon 4, which encodes part of the CC domain, seems to be a hotspot for missense variants (Table 1). In addition, the CARD14 variants that were shown to be most pathogenic, such as p.Glu138Ala, p.Glu142Lys, and p.Glu142Gly, are also encoded by exon 4 (
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ). Another strongly pathogenic variant, p.Gly117Ser, is encoded by exon 3 and leads to altered splicing of CARD14, resulting in the insertion of 22 additional amino acids between exons 3 and 4 (
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      ). Overexpression of the pathogenic missense CARD14 variants in primary keratinocytes resulted in enhanced NF-κB activation and increased production of several psoriasis-associated chemokines, such as CXCL8 and CCL20 (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Pierson K.C.
      • Yang C.F.
      • Joyce C.E.
      • et al.
      PSORS2 is due to mutations in CARD14.
      ). Therefore, it is generally believed that excessive activation of NF-κB and expression of NF-κB-responsive genes in keratinocytes by psoriasis-associated CARD14 variants can initiate an inflammatory reaction that attracts immune cells to the skin and culminates in psoriasis development. However, not all CARD14 variants that have been identified in patients with psoriasis and pityriasis rubra pilaris lead to excessive NF-κB activation. For instance, the variant p.Arg69Trp reduces NF-κB activation sevenfold compared with wild-type CARD14 (
      • Ammar M.
      • Jordan C.T.
      • Cao L.
      • Lim E.
      • Bouchlaka Souissi C.
      • Jrad A.
      • et al.
      CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts.
      ). These ambiguous effects on NF-κB suggest that CARD14 could be involved in additional signaling pathways or that basal NF-κB levels might be crucial to preserve skin homeostasis. Finally, p.Arg820Trp, a common polymorphism of CARD14 that is associated with psoriasis susceptibility, was shown to be enriched in patients who responded well to anti-TNF therapy, indicating that CARD14 variants might be used to stratify patients for optimal treatment strategies (
      • Coto-Segura P.
      • Gonzalez-Fernandez D.
      • Batalla A.
      • Gomez J.
      • Gonzalez-Lara L.
      • Queiro R.
      • et al.
      Common and rare CARD14 gene variants affect the anti-TNF response among Psoriasis patients.
      ,
      • Feng C.
      • Wang T.
      • Li S.J.
      • Fan Y.M.
      • Shi G.
      • Zhu K.J.
      CARD14 gene polymorphism c.C2458T (p.Arg820Trp) is associated with clinical features of psoriasis vulgaris in a Chinese cohort.
      ,
      • Gonzalez-Lara L.
      • Coto-Segura P.
      • Penedo A.
      • Eiris N.
      • Diaz M.
      • Santos-Juanes J.
      • et al.
      SNP rs11652075 in the CARD14 gene as a risk factor for psoriasis (PSORS2) in a Spanish cohort.
      ,
      • Jordan C.T.
      • Cao L.
      • Roberson E.D.
      • Duan S.
      • Helms C.A.
      • Nair R.P.
      • et al.
      Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.
      ,
      • Sugiura K.
      • Kitoh T.
      • Watanabe D.
      • Muto M.
      • Akiyama M.
      Childhood-onset PsA in Down syndrome with psoriasis susceptibility variant CARD14 rs11652075.
      ). Although further research is necessary to identify pathogenic CARD14 variants and their effects on CARD14 function, recent studies have provided some insight into CARD14-induced signaling events and how psoriasis-associated CARD14 variants may affect NF-κB activation.

      The CARD14-BCL10-MALT1 Complex in Keratinocytes

      Activated CARD14 and its homologues are known to bind the adapter protein B-cell lymphoma 10 (BCL10) via a CARD-CARD-mediated interaction (
      • Bertin J.
      • Wang L.
      • Guo Y.
      • Jacobson M.D.
      • Poyet J.L.
      • Srinivasula S.M.
      • et al.
      CARD11 and CARD14 are novel caspase recruitment domain (CARD)/membrane-associated guanylate kinase (MAGUK) family members that interact with BCL10 and activate NF-kappa B.
      ,
      • McAllister-Lucas L.M.
      • Inohara N.
      • Lucas P.C.
      • Ruland J.
      • Benito A.
      • Li Q.
      • et al.
      Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-kappaB induction.
      ,
      • Wang L.
      • Guo Y.
      • Huang W.J.
      • Ke X.
      • Poyet J.L.
      • Manji G.A.
      • et al.
      Card10 is a novel caspase recruitment domain/membrane-associated guanylate kinase family member that interacts with BCL10 and activates NF-kappa B.
      ). BCL10 is constitutively bound to mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) and has recently been shown to recruit MALT1 to activated CARD14, resulting in the formation of a CBM (CARD14-BLC10-MALT1) complex (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ,
      • Howes A.
      • O'Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ,
      • Lucas P.C.
      • Yonezumi M.
      • Inohara N.
      • McAllister-Lucas L.M.
      • Abazeed M.E.
      • Chen F.F.
      • et al.
      Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway.
      ,
      • Uren A.G.
      • O'Rourke K.
      • Aravind L.A.
      • Pisabarro M.T.
      • Seshagiri S.
      • Koonin E.V.
      • et al.
      Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma.
      ) (Figure 1). CARD14-induced CBM complex formation further culminates in the activation of NF-κB as well as of the MAP kinases p38 and JNK (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ). The formation of a CARD14-BCL10-MALT1 signaling complex in keratinocytes is reminiscent of the well-described CARD11-BCL10-MALT1 signaling complex that is formed in antigen receptor-stimulated lymphocytes. CBM complex assembly in lymphocytes leads to the recruitment of the ubiquitin ligase TRAF6, which mediates K63-linked polyubiquitination of itself, MALT1 and BCL10 (
      • Deng L.
      • Wang C.
      • Spencer E.
      • Yang L.
      • Braun A.
      • You J.
      • et al.
      Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain.
      ,
      • Oeckinghaus A.
      • Wegener E.
      • Welteke V.
      • Ferch U.
      • Arslan S.C.
      • Ruland J.
      • et al.
      Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation.
      ,
      • Sun L.
      • Deng L.
      • Ea C.K.
      • Xia Z.P.
      • Chen Z.J.
      The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes.
      ). These polyubiquitin chains serve as docking sites for the inhibitor of κB kinase complex (IKK), the linear ubiquitin chain assembly complex, and a TAK1-containing complex, resulting in the optimal activation of the IKK complex (
      • Afonina I.S.
      • Elton L.
      • Carpentier I.
      • Beyaert R.
      MALT1—a universal soldier: multiple strategies to ensure NF-kappaB activation and target gene expression.
      ,
      • Thome M.
      Multifunctional roles for MALT1 in T-cell activation.
      ). The activated IKK complex phosphorylates IκB, which is subsequently degraded by the proteasome, thus releasing NF-κB subunits into the nucleus to activate the transcription of target genes. Although the molecular signaling events downstream of the CARD14-BCL10-MALT1 signaling complex have not yet been described in keratinocytes, it can be expected that they are similar to those downstream of the CARD11-induced signaling described above (Figure 1).
      The molecular events that lead to the formation of a CARD14-BCL10-MALT1 signaling complex are still largely unclear. It has been suggested that, in unstimulated cells, CARD14 is kept in an autoinhibitory conformation by the inhibitory linker domain located between the CC and the PDZ domains (
      • Howes A.
      • O'Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ). Removal of the inhibitory domain of CARD14 abrogates the effect of psoriasis-associated activating point mutations on NF-κB induction (
      • Howes A.
      • O'Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ). Compared to wild-type CARD14 expression, overexpression of the p.Glu138Ala and p.Gly117Ser mutants enhances CBM complex formation, leading to increased NF-κB activation (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ,
      • Howes A.
      • O'Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ). Collectively, these data indicate that single point mutations in the CC domain of CARD14 result in conformational changes that affect inter- or intramolecular interactions crucial for CBM assembly.
      It has been shown that MALT1 can be activated by treatment of keratinocytes with the fungal cell wall component zymosan. Moreover, silencing of the zymosan-detecting C-type lectin receptor dectin-1, but not of TLR2 or its adaptor MyD88, strongly reduces MALT1 activity in keratinocytes (
      • Schmitt A.
      • Grondona P.
      • Maier T.
      • Brandle M.
      • Schonfeld C.
      • Jager G.
      • et al.
      MALT1 Protease activity controls the expression of inflammatory genes in keratinocytes upon zymosan stimulation.
      ). Interestingly, stimulation of dectin-1 in myeloid cells leads to the formation of a CARD9-containing CBM complex that is crucial for antifungal immune responses (
      • Gross O.
      • Gewies A.
      • Finger K.
      • Schafer M.
      • Sparwasser T.
      • Peschel C.
      • et al.
      Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity.
      ), suggesting the potential formation of a related CARD14-containing CBM complex in dectin-1-stimulated keratinocytes. How exactly dectin-1 activates the CBM complex in keratinocytes is thus far unclear. Dectin-1, like other immune receptors (e.g., T cell receptor, B cell receptor, and NKG2D), employs immunoreceptor tyrosine-based activation motifs (ITAMs) to initiate downstream signaling via Src kinases (
      • Thome M.
      Multifunctional roles for MALT1 in T-cell activation.
      ). In T cells, Src kinase activity eventually leads to the activation of PKCθ, which in turn phosphorylates and activates CARD11 (
      • Matsumoto R.
      • Wang D.
      • Blonska M.
      • Li H.
      • Kobayashi M.
      • Pappu B.
      • et al.
      Phosphorylation of CARMA1 plays a critical role in T cell receptor-mediated NF-kappaB activation.
      ,
      • Sommer K.
      • Guo B.
      • Pomerantz J.L.
      • Bandaranayake A.D.
      • Moreno-Garcia M.E.
      • Ovechkina Y.L.
      • et al.
      Phosphorylation of the CARMA1 linker controls NF-kappaB activation.
      ,
      • Thome M.
      Multifunctional roles for MALT1 in T-cell activation.
      ). In keratinocytes, PKC activation upon treatment with phorbol 12-myristate 13-acetate results in MALT1 activation that can be prevented by CARD14 silencing (
      • Schmitt A.
      • Grondona P.
      • Maier T.
      • Brandle M.
      • Schonfeld C.
      • Jager G.
      • et al.
      MALT1 Protease activity controls the expression of inflammatory genes in keratinocytes upon zymosan stimulation.
      ), suggesting also a regulatory role for PKC in the activation of CARD14. In addition, Src and PKC inhibition interferes with zymosan-induced MALT1 activation in keratinocytes. It is therefore tempting to speculate that dectin-1 leads to PKC-mediated phosphorylation and activation of CARD14, facilitating the formation of a CBM complex (Figure 1).

      Protease Activity and Substrates of MALT1

      Aside from its function as a scaffold protein in the CBM complex, MALT1 also acts as an arginine-specific protease and further fine-tunes the activation of the proinflammatory cascade. Although the caspase-like domain of MALT1 had already been described in 2000 (
      • Uren A.G.
      • O'Rourke K.
      • Aravind L.A.
      • Pisabarro M.T.
      • Seshagiri S.
      • Koonin E.V.
      • et al.
      Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma.
      ), its first substrates were only identified in 2008 by two independent groups (
      • Coornaert B.
      • Baens M.
      • Heyninck K.
      • Bekaert T.
      • Haegman M.
      • Staal J.
      • et al.
      T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20.
      ,
      • Rebeaud F.
      • Hailfinger S.
      • Posevitz-Fejfar A.
      • Tapernoux M.
      • Moser R.
      • Rueda D.
      • et al.
      The proteolytic activity of the paracaspase MALT1 is key in T cell activation.
      ). Because of its unique protease activity—MALT1 is the only known human paracaspase (
      • Hulpiau P.
      • Driege Y.
      • Staal J.
      • Beyaert R.
      MALT1 is not alone after all: identification of novel paracaspases.
      )—it seems to be a promising drug target for dampening excessive inflammatory signaling.
      So far, eight substrates of MALT1 have been described in stimulated lymphocytes: A20, BCL10, CYLD, RelB, regnase-1, roquin, HOIL-1, and MALT1 itself (
      • Afonina I.S.
      • Elton L.
      • Carpentier I.
      • Beyaert R.
      MALT1—a universal soldier: multiple strategies to ensure NF-kappaB activation and target gene expression.
      ,
      • Hailfinger S.
      • Lenz G.
      • Thome M.
      Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase.
      ,
      • Klein T.
      • Fung S.Y.
      • Renner F.
      • Blank M.A.
      • Dufour A.
      • Kang S.
      • et al.
      The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-kappaB signalling.
      ). Cleavage of these substrates affects various processes, such as NF-κB (A20, RelB, HOIL-1) and JNK (CYLD) activation, linear ubiquitination (HOIL-1), mRNA stability (regnase-1, roquin), and cell adhesion (BCL10). Because MALT1 can regulate inflammatory signaling and immune responses by cleaving these substrates, its proteolytic activity is subject to several regulatory mechanisms. Dimerization and monoubiquitination of MALT1 are necessary to adopt and maintain its catalytically active conformation (
      • Cabalzar K.
      • Pelzer C.
      • Wolf A.
      • Lenz G.
      • Iwaszkiewicz J.
      • Zoete V.
      • et al.
      Monoubiquitination and activity of the paracaspase MALT1 requires glutamate 549 in the dimerization interface.
      ,
      • Pelzer C.
      • Cabalzar K.
      • Wolf A.
      • Gonzalez M.
      • Lenz G.
      • Thome M.
      The protease activity of the paracaspase MALT1 is controlled by monoubiquitination.
      ,
      • Wiesmann C.
      • Leder L.
      • Blank J.
      • Bernardi A.
      • Melkko S.
      • Decock A.
      • et al.
      Structural determinants of MALT1 protease activity.
      ). Thus, formation of supramolecular filamentous CBM complexes not only activates NF-κB signaling but also drives MALT1 proteolytic activity through oligomerization of MALT1 (
      • Qiao Q.
      • Yang C.
      • Zheng C.
      • Fontan L.
      • David L.
      • Yu X.
      • et al.
      Structural architecture of the CARMA1/Bcl10/MALT1 signalosome: nucleation-induced filamentous assembly.
      ).
      Recently, a distinct role for MALT1 protease activity has emerged in inflammatory signaling in keratinocytes. Certain stimuli, such as zymosan and Staphylococcus aureus, were able to induce MALT1 proteolytic activity in keratinocytes, resulting in the cleavage of CYLD, RelB, A20, and regnase-1 (
      • Schmitt A.
      • Grondona P.
      • Maier T.
      • Brandle M.
      • Schonfeld C.
      • Jager G.
      • et al.
      MALT1 Protease activity controls the expression of inflammatory genes in keratinocytes upon zymosan stimulation.
      ) (Figure 1). In addition, overexpression of CARD14 in keratinocytes was shown to promote processing of MALT1 substrates (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ), which was further enhanced by the psoriasis-associated CARD14 versions p.Gly117Ser and p.Glu138Ala, highlighting the pathological relevance of CARD14 mutations in psoriasis (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ,
      • Howes A.
      • O'Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ). Inhibition of MALT1 protease activity in keratinocytes reduced the expression of important CARD14-regulated proinflammatory cytokines (e.g., TNF, IL-1β, and IL-17C), chemokines (e.g., CXCL8 and CCL20), and antimicrobial peptides (e.g., HBD-2 and S100A7), pointing to an important role for MALT1 in the immune response in the skin (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ,
      • Schmitt A.
      • Grondona P.
      • Maier T.
      • Brandle M.
      • Schonfeld C.
      • Jager G.
      • et al.
      MALT1 Protease activity controls the expression of inflammatory genes in keratinocytes upon zymosan stimulation.
      ). Interestingly, it was also shown that A20 and CYLD, two substrates of MALT1 that have been associated with psoriasis (
      • Nititham J.
      • Taylor K.E.
      • Gupta R.
      • Chen H.
      • Ahn R.
      • Liu J.
      • et al.
      Meta-analysis of the TNFAIP3 region in psoriasis reveals a risk haplotype that is distinct from other autoimmune diseases.
      ,
      • Oudot T.
      • Lesueur F.
      • Guedj M.
      • de Cid R.
      • McGinn S.
      • Heath S.
      • et al.
      An association study of 22 candidate genes in psoriasis families reveals shared genetic factors with other autoimmune and skin disorders.
      ,
      • Tejasvi T.
      • Stuart P.E.
      • Chandran V.
      • Voorhees J.J.
      • Gladman D.D.
      • Rahman P.
      • et al.
      TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis.
      ), can inhibit CARD14-mediated signaling (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ). In this way, the cleavage of these negative regulators by MALT1 may promote optimal CARD14-mediated signaling. These findings imply that the proteolytic activity of MALT1 could contribute to the pathology of psoriasis.

      Therapeutic Potential of MALT1 Inhibitors in Psoriasis and Future Perspectives

      Currently, there is no cure for psoriasis, but several treatments targeting the immune response and the differentiation status of keratinocytes can alleviate its symptoms. Conventional therapies, including glucocorticoids, fumarates, vitamin D derivatives, and phototherapy, are effective in treating mild cases but often induce unwanted side effects in patients. Recently, biological entities that target central cytokines in psoriasis, such as TNF, IL-17, and IL-12/IL-23, have emerged and often show better efficacy than conventional therapies in severe cases. However, not all patients are responsive to these cost-intensive treatments, highlighting the need for alternative treatment options (
      • Deng Y.
      • Chang C.
      • Lu Q.
      The inflammatory response in psoriasis: a comprehensive review.
      ).
      The ability of CARD14 and particularly its psoriasis-associated mutants to activate the protease function of MALT1 and proinflammatory gene expression in keratinocytes provides a rationale for MALT1 inhibitors in psoriasis treatment (
      • Afonina I.S.
      • Van Nuffel E.
      • Baudelet G.
      • Driege Y.
      • Kreike M.
      • Staal J.
      • et al.
      The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes.
      ,
      • Howes A.
      • O'Sullivan P.A.
      • Breyer F.
      • Ghose A.
      • Cao L.
      • Krappmann D.
      • et al.
      Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-kappaB activation.
      ). Many CARD14-regulated genes are key players in the pathogenesis of psoriasis and are targets of current standard treatment regimens (e.g., anti-TNF biologics). Although there are at present no MALT1 inhibitors in the clinic, several groups of small molecule inhibitors have been published and patented, thus providing a pool of potential lead structures for further clinical development (
      • Fontan L.
      • Yang C.
      • Kabaleeswaran V.
      • Volpon L.
      • Osborne M.J.
      • Beltran E.
      • et al.
      MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo.
      ,
      • Lim S.M.
      • Jeong Y.
      • Lee S.
      • Im H.
      • Tae H.S.
      • Kim B.G.
      • et al.
      Identification of beta-lapachone analogs as novel MALT1 inhibitors to treat an aggressive subtype of diffuse large B-cell lymphoma.
      ,
      • Nagel D.
      • Spranger S.
      • Vincendeau M.
      • Grau M.
      • Raffegerst S.
      • Kloo B.
      • et al.
      Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL.
      ). MALT1 inhibitors have been successfully tested preclinically in vitro and in vivo in the treatment of a subtype of diffuse large B-cell lymphoma and in a mouse model of multiple sclerosis (
      • Fontan L.
      • Yang C.
      • Kabaleeswaran V.
      • Volpon L.
      • Osborne M.J.
      • Beltran E.
      • et al.
      MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo.
      ,
      • Mc Guire C.
      • Elton L.
      • Wieghofer P.
      • Staal J.
      • Voet S.
      • Demeyer A.
      • et al.
      Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis.
      ,
      • Nagel D.
      • Spranger S.
      • Vincendeau M.
      • Grau M.
      • Raffegerst S.
      • Kloo B.
      • et al.
      Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL.
      ). Because CBM activation in keratinocytes leads to MALT1-dependent inactivation of A20, CYLD, RelB, and the endonuclease regnase-1, MALT1 inhibition will likely result in reduced NF-κB and AP-1 activity and decreased mRNA stability of various proinflammatory target genes.
      Potential side effects of MALT1 inhibition can be predicted from MALT1 activity deficient mice. MALT1 knockout mice are viable and develop normally but suffer from severe immunodeficiency, including proliferation and activation defects in B and T cells after antigen receptor stimulation as well as reduced numbers of marginal zone and peritoneal B1 cells (
      • Ruefli-Brasse A.A.
      • French D.M.
      • Dixit V.M.
      Regulation of NF-kappaB-dependent lymphocyte activation and development by paracaspase.
      ,
      • Ruland J.
      • Duncan G.S.
      • Wakeham A.
      • Mak T.W.
      Differential requirement for Malt1 in T and B cell antigen receptor signaling.
      ). Surprisingly, mice expressing protease-inactive MALT1 additionally suffer from spontaneous autoimmunity (
      • Bornancin F.
      • Renner F.
      • Touil R.
      • Sic H.
      • Kolb Y.
      • Touil-Allaoui I.
      • et al.
      Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation.
      ,
      • Gewies A.
      • Gorka O.
      • Bergmann H.
      • Pechloff K.
      • Petermann F.
      • Jeltsch K.M.
      • et al.
      Uncoupling Malt1 threshold function from paracaspase activity results in destructive autoimmune inflammation.
      ,
      • Jaworski M.
      • Marsland B.J.
      • Gehrig J.
      • Held W.
      • Favre S.
      • Luther S.A.
      • et al.
      Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity.
      ,
      • Yu J.W.
      • Hoffman S.
      • Beal A.M.
      • Dykon A.
      • Ringenberg M.A.
      • Hughes A.C.
      • et al.
      MALT1 protease activity is required for innate and adaptive immune responses.
      ). Whereas T cells from MALT1 knockout mice show no proliferation and IL-2 production upon stimulation, T cells from MALT1 protease-dead knock-in mice still respond partially due to the preserved scaffold function of MALT1. Because the development of regulatory T cells is strongly decreased in the knock-in mice, the residual activity of T cells might be enough to drive autoimmunity. Whether the effect on regulatory T cell development is relevant in human patients is unclear but could most likely be circumvented by the topical administration of a therapeutic MALT1 inhibitor. Thus, further studies are needed to validate the potential of MALT1 inhibitors in vivo in psoriasis-like mouse models. New insights could also come from CARD14 knockout or CARD14 mutant-expressing mice or from the keratinocyte-specific expression of a protease-inactive MALT1. In addition, the identification of other receptors driving CBM complex formation will help to further elucidate the role of MALT1 in keratinocytes. Because CARD14 mutations in psoriasis are relatively rare, the analysis of human psoriasis biopsies for active MALT1 will clarify the importance of the CBM pathway in this disease. MALT1 inhibition seems to be a particularly promising treatment strategy because it can tackle psoriasis in two ways: first by decreasing the expression of proinflammatory target genes in keratinocytes and secondly by blocking the activation of immune cells in the skin.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      This work was supported by grants from the Emmy-Noether Program and SFB 685 of the German Research Foundation, the AID network of the German Ministry for Education and Research, the ICEPHA and Excellence Initiative of the University of Tuebingen (to SH and KSO) as well as of the Fund for Scientific Research Flanders (FWO), the Belgian Foundation Against Cancer, Interuniversity Attraction Poles, Concerted Research Actions (GOA), and the Group-ID Multidisciplinary Research Partnership of Ghent University (to RB). EVN and IA are supported by a predoctoral and postdoctoral fellowship, respectively, from the FWO.

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