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Photosensitivity and cGAS-Dependent IFN-1 Activation in Patients with Lupus and TREX1 Deficiency

Published:August 13, 2021DOI:https://doi.org/10.1016/j.jid.2021.04.037
      The exonuclease TREX1 safeguards the cells against DNA accumulation in the cytosol and thereby prevents innate immune activation and autoimmunity. TREX1 mutations lead to chronic DNA damage and cell-intrinsic IFN-1 response. Associated disease phenotypes include Aicardi‒Goutières syndrome, familial chilblain lupus, and systemic lupus erythematosus. Given the role of UV light in lupus pathogenesis, we assessed sensitivity to UV light in patients with lupus and TREX1 mutation by phototesting, which revealed enhanced photosensitivity. TREX1-deficient fibroblasts and keratinocytes generated increased levels of ROS in response to UV irradiation as well as increased levels of 8-oxo-guanine lesions after oxidative stress. Likewise, the primary UV-induced DNA lesions cyclobutane pyrimidine dimers were induced more strongly in TREX1-deficient cells. Further analysis revealed that single-stranded DNA regions, frequently formed during DNA replication and repair, promote cyclobutane pyrimidine dimer formation. Together, this resulted in a strong UV-induced DNA damage response that was associated with a cGAS-dependent IFN-1 activation. In conclusion, these findings link chronic DNA damage to photosensitivity and IFN-1 production in TREX1 deficiency and explain the induction of disease flares on UV exposure in patients with lupus and TREX1 mutation.

      Abbreviations:

      AGS (Aicardi‒Goutières syndrome), CPD (cyclobutane pyrimidine dimer), FCL (familial chilblain lupus), H2O2 (hydrogen peroxide), HC (healthy control), ISG (IFN-1–stimulated gene), KC (keratinocyte), LE (lupus erythematosus), siRNA (small interfering RNA), SLE (systemic lupus erythematosus), ssDNA (single-stranded DNA), SSR (solar simulated irradiation)
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      References

        • Ablasser A.
        • Goldeck M.
        • Cavlar T.
        • Deimling T.
        • Witte G.
        • Röhl I.
        • et al.
        cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING.
        Nature. 2013; 498: 380-384
        • Ablasser A.
        • Hemmerling I.
        • Schmid-Burgk J.L.
        • Behrendt R.
        • Roers A.
        • Hornung V.
        TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner.
        J Immunol. 2014; 192: 5993-5997
        • Crow Y.J.
        • Hayward B.E.
        • Parmar R.
        • Robins P.
        • Leitch A.
        • Ali M.
        • et al.
        Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus.
        Nat Genet. 2006; 38: 917-920
        • Gehrke N.
        • Mertens C.
        • Zillinger T.
        • Wenzel J.
        • Bald T.
        • Zahn S.
        • et al.
        Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing.
        Immunity. 2013; 39: 482-495
        • Gibson B.A.
        • Kraus W.L.
        New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs.
        Nat Rev Mol Cell Biol. 2012; 13: 411-424
        • Glück S.
        • Guey B.
        • Gulen M.F.
        • Wolter K.
        • Kang T.W.
        • Schmacke N.A.
        • et al.
        Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence.
        Nat Cell Biol. 2017; 19: 1061-1070
        • Grieves J.L.
        • Fye J.M.
        • Harvey S.
        • Grayson J.M.
        • Hollis T.
        • Perrino F.W.
        Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease.
        Proc Natl Acad Sci USA. 2015; 112: 5117-5122
        • Grimsrud P.A.
        • Xie H.
        • Griffin T.J.
        • Bernlohr D.A.
        Oxidative stress and covalent modification of protein with bioactive aldehydes.
        J Biol Chem. 2008; 283: 21837-21841
        • Günther C.
        Nucleic acid immunity in the pathogenesis of cutaneous lupus erythematosus.
        Front Immunol. 2019; 10: 1636
        • Günther C.
        • Berndt N.
        • Wolf C.
        • Lee-Kirsch M.A.
        Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3' repair exonuclease 1 (TREX1).
        JAMA Dermatol. 2015; 151: 426-431
        • Günther C.
        • Kind B.
        • Reijns M.A.
        • Berndt N.
        • Martinez-Bueno M.
        • Wolf C.
        • et al.
        Defective removal of ribonucleotides from DNA promotes systemic autoimmunity.
        J Clin Invest. 2015; 125: 413-424
        • Günther C.
        • Schmidt F.
        • König N.
        • Lee-Kirsch M.A.
        Typ-I-Interferonopathien. Durch typ-1-interferone bedingte entzündliche systemerkrankungen [Type I interferonopathies. Systemic inflammatory diseases triggered by type I interferons].
        Z Rheumatol. 2016; 75 ([in German]): 134-140
        • Johnson A.T.
        • Wiest O.
        Structure and dynamics of poly(T) single-strand DNA: implications toward CPD formation.
        J Phys Chem B. 2007; 111: 14398-14404
        • Lee-Kirsch M.A.
        The type I interferonopathies.
        Annu Rev Med. 2017; 68: 297-315
        • Lee-Kirsch M.A.
        • Chowdhury D.
        • Harvey S.
        • Gong M.
        • Senenko L.
        • Engel K.
        • et al.
        A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.
        J Mol Med (Berl). 2007; 85: 531-537
        • Lee-Kirsch M.A.
        • Gong M.
        • Chowdhury D.
        • Senenko L.
        • Engel K.
        • Lee Y.A.
        • et al.
        Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus.
        Nat Genet. 2007; 39: 1065-1067
        • Lee-Kirsch M.A.
        • Gong M.
        • Schulz H.
        • Rüschendorf F.
        • Stein A.
        • Pfeiffer C.
        • et al.
        Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p.
        Am J Hum Genet. 2006; 79: 731-737
        • Lim K.W.
        • Phan A.T.
        Structural basis of DNA quadruplex-duplex junction formation.
        Angew Chem Int Ed Engl. 2013; 52: 8566-8569
        • Lundin C.
        • North M.
        • Erixon K.
        • Walters K.
        • Jenssen D.
        • Goldman A.S.
        • et al.
        Methyl methanesulfonate (MMS) produces heat-labile DNA damage but no detectable in vivo DNA double-strand breaks [published correction appears in Nucleic Acids Res 2012;40:5794].
        Nucleic Acids Res. 2005; 33: 3799-3811
        • Mackenzie K.J.
        • Carroll P.
        • Martin C.A.
        • Murina O.
        • Fluteau A.
        • Simpson D.J.
        • et al.
        cGAS surveillance of micronuclei links genome instability to innate immunity.
        Nature. 2017; 548: 461-465
        • Marti T.M.
        • Hefner E.
        • Feeney L.
        • Natale V.
        • Cleaver J.E.
        H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double-strand breaks.
        Proc Natl Acad Sci USA. 2006; 103: 9891-9896
        • Mazur D.J.
        • Perrino F.W.
        Excision of 3' termini by the Trex1 and TREX2 3'-->5' exonucleases. Characterization of the recombinant proteins.
        J Biol Chem. 2001; 276: 17022-17029
        • Meas R.
        • Burak M.J.
        • Sweasy J.B.
        DNA repair and systemic lupus erythematosus.
        DNA Repair (Amst). 2017; 56: 174-182
        • Peschke K.
        • Friebe F.
        • Zimmermann N.
        • Wahlicht T.
        • Schumann T.
        • Achleitner M.
        • et al.
        Deregulated type I IFN response in TREX1-associated familial chilblain lupus [published corrections appears in J Invest Dermatol 2014;134] [published correction appears in J Invest Dermatol 2014;134:2475].
        J Invest Dermatol. 2014; 134: 1456-1459
        • Ramantani G.
        • Kohlhase J.
        • Hertzberg C.
        • Innes A.M.
        • Engel K.
        • Hunger S.
        • et al.
        Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome.
        Arthritis Rheum. 2010; 62: 1469-1477
        • Rastogi R.P.
        • Richa
        • Kumar A.
        • Tyagi M.B.
        • Sinha R.P.
        Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair.
        J Nucleic Acids. 2010; 2010: 592980
        • Scholtissek B.
        • Zahn S.
        • Maier J.
        • Klaeschen S.
        • Braegelmann C.
        • Hoelzel M.
        • et al.
        Immunostimulatory endogenous nucleic acids drive the lesional inflammation in cutaneous lupus erythematosus.
        J Invest Dermatol. 2017; 137: 1484-1492
        • Wolf C.
        • Rapp A.
        • Berndt N.
        • Staroske W.
        • Schuster M.
        • Dobrick-Mattheuer M.
        • et al.
        RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA.
        Nat Commun. 2016; 7: 11752
        • Wu Z.
        • Delaglio F.
        • Tjandra N.
        • Zhurkin V.B.
        • Bax A.
        Overall structure and sugar dynamics of a DNA dodecamer from homo- and heteronuclear dipolar couplings and 31P chemical shift anisotropy.
        J Biomol NMR. 2003; 26: 297-315
        • Yang Y.G.
        • Lindahl T.
        • Barnes D.E.
        Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease.
        Cell. 2007; 131: 873-886
        • Yu Q.
        • Katlinskaya Y.V.
        • Carbone C.J.
        • Zhao B.
        • Katlinski K.V.
        • Zheng H.
        • et al.
        DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function.
        Cell Rep. 2015; 11: 785-797
        • Zimmermann N.
        • Wolf C.
        • Schwenke R.
        • Lüth A.
        • Schmidt F.
        • Engel K.
        • et al.
        Assessment of clinical response to Janus kinase inhibition in patients with familial chilblain lupus and TREX1 mutation.
        JAMA Dermatol. 2019; 155: 342-346

      Supplementary References

        • Günther C.
        • Berndt N.
        • Wolf C.
        • Lee-Kirsch M.A.
        Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3' repair exonuclease 1 (TREX1).
        JAMA Dermatol. 2015; 151: 426-431
        • Günther C.
        • Kind B.
        • Reijns M.A.
        • Berndt N.
        • Martinez-Bueno M.
        • Wolf C.
        • et al.
        Defective removal of ribonucleotides from DNA promotes systemic autoimmunity.
        J Clin Invest. 2015; 125: 413-424
      1. Knuschke P, Krins A. UV-Personendosimetrie Teil B: Mit Verwendung des Polysulfonfilms als UV-Sensor. Schlussbericht BMBF-Vorhaben 07UVB54B. Standort Univeristätsbibliothek Hannover Techn Informationsbibliothek F 00 B. 2000; 15442000.

        • Kretschmer S.
        • Wolf C.
        • König N.
        • Staroske W.
        • Guck J.
        • Häusler M.
        • et al.
        SAMHD1 prevents autoimmunity by maintaining genome stability.
        Ann Rheum Dis. 2015; 74: e17
        • Lee-Kirsch M.A.
        • Gong M.
        • Chowdhury D.
        • Senenko L.
        • Engel K.
        • Lee Y.A.
        • et al.
        Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus.
        Nat Genet. 2007; 39: 1065-1067
        • Lee-Kirsch M.A.
        • Gong M.
        • Schulz H.
        • Rüschendorf F.
        • Stein A.
        • Pfeiffer C.
        • et al.
        Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p.
        Am J Hum Genet. 2006; 79: 731-737
        • Wolf C.
        • Rapp A.
        • Berndt N.
        • Staroske W.
        • Schuster M.
        • Dobrick-Mattheuer M.
        • et al.
        RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA.
        Nat Commun. 2016; 7: 11752