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HSF1 dependent autophagy activation contributes to the survival of melanocytes under oxidative stress in vitiligo

Published:November 12, 2021DOI:https://doi.org/10.1016/j.jid.2021.11.007

      ABSTRACT

      Autophagy plays a protective role in the oxidative stress-induced melanocyte death. Dysregulated autophagy increases the sensitivity of melanocytes in response to oxidative damage and promotes the melanocyte degeneration in vitiligo. However, the molecular mechanism underlying this process is not fully understood. Here, using RNA-Seq technology, we compared the transcriptome change between normal and vitiligo melanocytes with or without treatment of oxidative stress. We found that autophagy-related protein 5 and 12 (Atg5 and Atg12), the critical components for autophagosome formation, were significantly reduced in vitiligo melanocytes under oxidative stress. Mechanistically, heat shock factor 1 (HSF1) is the prime transcription factor for both Atg5 and Atg12, accounting for the reduced level of Atg5 and Atg12 in vitiligo melanocytes. Deficiency of HSF1 led to accumulation of intracellular reactive oxygen species (ROS), imbalance of mitochondrion membrane potential and apoptosis in melanocytes exposure to oxidative stress. Further, overexpression of HSF1 could ameliorate oxidative stress-induced melanocytes death by activation of autophagy through upregulating Atg5 and Atg12. These findings suggested targeting HSF1-Atg5/12 axis could prevent oxidative stress-induced melanocyte death and may be used as therapeutic strategies for vitiligo treatment.

      Key words

      Abbreviations used:

      Atg5 (autophagy-related protein 5), Atg12 (autophagy-related protein 12), HSF1 (heat shock factor 1), Atg7 (autophagy-related protein 7), GATA4 (GATA Binding Protein 4), ATG9B (autophagy-related protein 9B), HSPs (heat shock proteins), qRT-PCR (quantitative real-time PCR), PIG3V (vitiligo melanocyte cell line), PIG1 (normal human melanocyte cell line), DEGs (differentially expressed genes), Baf-A1 (Bafilomycin A1)
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      REFERENCE

        • Acharya P.
        • Mathur M.
        Interleukin-17 level in patients with vitiligo: A systematic review and meta-analysis.
        Australas J Dermatol. 2020; 61: e208-e212
        • Agarwal S.
        • Ganesh S.
        Perinuclear mitochondrial clustering, increased ROS levels, and HIF1 are required for the activation of HSF1 by heat stress.
        J Cell Sci. 2020; 133
        • Bhatia V.
        • Sharma S.
        Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer's disease.
        J Neurol Sci. 2021; 421: 117253
        • Bickers D.R.
        • Athar M.
        Oxidative stress in the pathogenesis of skin disease.
        J Invest Dermatol. 2006; 126: 2565-2575
        • Carranza A.D.V.
        • Saragusti A.
        • Chiabrando G.A.
        • Carrari F.
        • Asis R.
        Effects of chlorogenic acid on thermal stress tolerance in C. elegans via HIF-1, HSF-1 and autophagy.
        Phytomedicine. 2020; 66: 153132
        • Cui T.
        • Zhang W.
        • Li S.
        • Chen X.
        • Chang Y.
        • Yi X.
        • et al.
        Oxidative Stress-Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo.
        J Invest Dermatol. 2019; 139: 2174-21784 e4
        • Dang X.
        • Du G.
        • Hu W.
        • Ma L.
        • Wang P.
        • Li Y.
        Peroxisome proliferator-activated receptor gamma coactivator-1alpha/HSF1 axis effectively alleviates lipopolysaccharide-induced acute lung injury via suppressing oxidative stress and inflammatory response.
        J Cell Biochem. 2019; 120: 544-551
        • Dell'Anna M.L.
        • Ottaviani M.
        • Albanesi V.
        • Vidolin A.P.
        • Leone G.
        • Ferraro C.
        • et al.
        Membrane lipid alterations as a possible basis for melanocyte degeneration in vitiligo.
        J Invest Dermatol. 2007; 127: 1226-1233
        • Dikic I.
        • Elazar Z.
        Mechanism and medical implications of mammalian autophagy.
        Nat Rev Mol Cell Biol. 2018; 19: 349-364
        • Dong B.
        • Jaeger A.M.
        • Thiele D.J.
        Inhibiting Heat Shock Factor 1 in Cancer: A Unique Therapeutic Opportunity.
        Trends Pharmacol Sci. 2019; 40: 986-1005
        • Gomez-Pastor R.
        • Burchfiel E.T.
        • Thiele D.J.
        Regulation of heat shock transcription factors and their roles in physiology and disease.
        Nat Rev Mol Cell Biol. 2018; 19: 4-19
        • Han F.
        • Ren H.
        • Tang M.
        • Zhu Y.
        • Guan H.
        Clinical Reasoning: A 47-year-old man with rapidly progressive ataxia and vitiligo.
        Neurology. 2020; 94: e1664-e1669
        • He Y.
        • Li S.
        • Zhang W.
        • Dai W.
        • Cui T.
        • Wang G.
        • et al.
        Dysregulated autophagy increased melanocyte sensitivity to H2O2-induced oxidative stress in vitiligo.
        Sci Rep. 2017; 7: 42394
        • Ichimura Y.
        • Waguri S.
        • Sou Y.S.
        • Kageyama S.
        • Hasegawa J.
        • Ishimura R.
        • et al.
        Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy.
        Mol Cell. 2013; 51: 618-631
        • Jian Z.
        • Li K.
        • Liu L.
        • Zhang Y.
        • Zhou Z.
        • Li C.
        • et al.
        Heme oxygenase-1 protects human melanocytes from H2O2-induced oxidative stress via the Nrf2-ARE pathway.
        J Invest Dermatol. 2011; 131: 1420-1427
        • Kim M.
        • Sandford E.
        • Gatica D.
        • Qiu Y.
        • Liu X.
        • Zheng Y.
        • et al.
        Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.
        Elife. 2016; 5
        • Laddha N.C.
        • Dwivedi M.
        • Mansuri M.S.
        • Gani A.R.
        • Ansarullah M.
        • Ramachandran A.V.
        • et al.
        Vitiligo: interplay between oxidative stress and immune system.
        Exp Dermatol. 2013; 22: 245-250
        • Latorraca L.B.
        • Feitosa W.B.
        • Mariano C.
        • Moura M.T.
        • Fontes P.K.
        • Nogueira M.F.G.
        • et al.
        Autophagy is a pro-survival adaptive response to heat shock in bovine cumulus-oocyte complexes.
        Sci Rep. 2020; 10: 13711
        • Li J.G.
        • Chu J.
        • Pratico D.
        Downregulation of autophagy by 12/15Lipoxygenase worsens the phenotype of an Alzheimer's disease mouse model with plaques, tangles, and memory impairments.
        Mol Psychiatry. 2021; 26: 604-613
        • Li X.S.
        • Tang X.Y.
        • Su W.
        • Li X.
        Vitexin protects melanocytes from oxidative stress via activating MAPK-Nrf2/ARE pathway.
        Immunopharmacol Immunotoxicol. 2020; 42: 594-603
        • Liu H.
        • He Z.
        • Simon H.U.
        Protective role of autophagy and autophagy-related protein 5 in early tumorigenesis.
        J Mol Med (Berl). 2015; 93: 159-164
        • Mosenson J.A.
        • Flood K.
        • Klarquist J.
        • Eby J.M.
        • Koshoffer A.
        • Boissy R.E.
        • et al.
        Preferential secretion of inducible HSP70 by vitiligo melanocytes under stress.
        Pigment Cell Melanoma Res. 2014; 27: 209-220
        • Mosenson J.A.
        • Zloza A.
        • Nieland J.D.
        • Garrett-Mayer E.
        • Eby J.M.
        • Huelsmann E.J.
        • et al.
        Mutant HSP70 reverses autoimmune depigmentation in vitiligo.
        Sci Transl Med. 2013; 5: 174ra28
        • Patel D.C.
        • Evans A.V.
        • Hawk J.L.
        Topical pseudocatalase mousse and narrowband UVB phototherapy is not effective for vitiligo: an open, single-centre study.
        Clin Exp Dermatol. 2002; 27: 641-644
        • Qiao Z.
        • Xu Z.
        • Xiao Q.
        • Yang Y.
        • Ying J.
        • Xiang L.
        • et al.
        Dysfunction of ATG7-dependent autophagy dysregulates the antioxidant response and contributes to oxidative stress-induced biological impairments in human epidermal melanocytes.
        Cell Death Discov. 2020; 6: 31
        • Ramkumar A.
        • Murthy D.
        • Raja D.A.
        • Singh A.
        • Krishnan A.
        • Khanna S.
        • et al.
        Classical autophagy proteins LC3B and ATG4B facilitate melanosome movement on cytoskeletal tracks.
        Autophagy. 2017; 13: 1331-1347
        • Romanov J.
        • Walczak M.
        • Ibiricu I.
        • Schuchner S.
        • Ogris E.
        • Kraft C.
        • et al.
        Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation.
        EMBO J. 2012; 31: 4304-4317
        • Sastry K.S.
        • Naeem H.
        • Mokrab Y.
        • Chouchane A.I.
        RNA-seq Reveals Dysregulation of Novel Melanocyte Genes upon Oxidative Stress: Implications in Vitiligo Pathogenesis.
        Oxid Med Cell Longev. 2019; 2019: 2841814
        • Shi Y.
        • Mosser D.D.
        • Morimoto R.I.
        Molecular chaperones as HSF1-specific transcriptional repressors.
        Genes Dev. 1998; 12: 654-666
        • Singh M.
        • Mansuri M.S.
        • Kadam A.
        • Palit S.P.
        • Dwivedi M.
        • Laddha N.C.
        • et al.
        Tumor Necrosis Factor-alpha affects melanocyte survival and melanin synthesis via multiple pathways in vitiligo.
        Cytokine. 2021; 140: 155432
        • Wang X.L.
        • Feng S.T.
        • Wang Y.T.
        • Yuan Y.H.
        • Li Z.P.
        • Chen N.H.
        • et al.
        Mitophagy, a Form of Selective Autophagy, Plays an Essential Role in Mitochondrial Dynamics of Parkinson's Disease.
        Cell Mol Neurobiol. 2021;
        • Watanabe Y.
        • Tsujimura A.
        • Taguchi K.
        • Tanaka M.
        HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis.
        Autophagy. 2017; 13: 133-148
        • Yi X.
        • Guo W.
        • Shi Q.
        • Yang Y.
        • Zhang W.
        • Chen X.
        • et al.
        SIRT3-Dependent Mitochondrial Dynamics Remodeling Contributes to Oxidative Stress-Induced Melanocyte Degeneration in Vitiligo.
        Theranostics. 2019; 9: 1614-1633
        • Yu L.
        • Chen Y.
        • Tooze S.A.
        Autophagy pathway: Cellular and molecular mechanisms.
        Autophagy. 2018; 14: 207-215
        • Yuksel E.P.
        • Aydin F.
        • Senturk N.
        • Canturk T.
        • Turanli A.Y.
        Comparison of the efficacy of narrow band ultraviolet B and narrow band ultraviolet B plus topical catalase-superoxide dismutase treatment in vitiligo patients.
        Eur J Dermatol. 2009; 19: 341-344
        • Zhang C.F.
        • Gruber F.
        • Ni C.
        • Mildner M.
        • Koenig U.
        • Karner S.
        • et al.
        Suppression of autophagy dysregulates the antioxidant response and causes premature senescence of melanocytes.
        J Invest Dermatol. 2015; 135: 1348-1357
        • Zhao P.
        • Li T.
        • Li Z.
        • Cao L.
        • Wang Y.
        • Wang Y.
        • et al.
        Preparation of Gold Nanoparticles and Its Effect on Autophagy and Oxidative Stress in Chronic Kidney Disease Cell Model.
        J Nanosci Nanotechnol. 2021; 21: 1266-1271
        • Zhu W.
        • Zhao Z.
        • Cheng B.
        The role of autophagy in skin pigmentation.
        Eur J Dermatol. 2020; 30: 655-662