title: Suppression of autophagy dysregulates the antioxidant response and causes premature senescence of melanocytes.
abstract: Autophagy is the central cellular mechanism for delivering organelles and cytoplasm to lysosomes for degradation and recycling of their molecular components. To determine the contribution of autophagy to melanocyte (MC) biology, we inactivated the essential autophagy gene Atg7 specifically in MCs using the Cre-loxP system. This gene deletion efficiently suppressed a key step in autophagy, lipidation of microtubule-associated protein 1 light chain 3 beta (LC3), in MCs and induced slight hypopigmentation of the epidermis in mice. The melanin content of hair was decreased by 10-15% in mice with autophagy-deficient MC as compared with control animals. When cultured in vitro, MCs from mutant and control mice produced equal amounts of melanin per cell. However, Atg7-deficient MCs entered into premature growth arrest and accumulated reactive oxygen species (ROS) damage, ubiquitinated proteins, and the multi-functional adapter protein SQSTM1/p62. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent expression of NAD(P)H dehydrogenase, quinone 1, and glutathione S-transferase Mu 1 was increased, indicating a contribution of autophagy to redox homeostasis in MCs. In summary, the results of our study suggest that Atg7-dependent autophagy is dispensable for melanogenesis but necessary for achieving the full proliferative capacity of MCs.
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Department of Dermatology, Huashan Hospital, Fu Dan University, Shanghai, China.
authors.forename: Cheng-Feng
authors.initials: CF
authors.lastname: Zhang
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: florian.gruber@meduniwien.ac.at.
authors.forename: Florian
authors.initials: F
authors.lastname: Gruber
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Department of Dermatology, Huashan Hospital, Fu Dan University, Shanghai, China.
authors.forename: Chunya
authors.initials: C
authors.lastname: Ni
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Mildner
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Koenig
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Karner
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Caterina
authors.initials: C
authors.lastname: Barresi
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Rossiter
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Marie-Sophie
authors.initials: MS
authors.lastname: Narzt
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Biotechnology of Skin Aging, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ionela M
authors.initials: IM
authors.lastname: Nagelreiter
authors.affiliation: Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, Orsay, France; CNRS UMR3347, Orsay, France; INSERM U1021, Orsay, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.affiliation: Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, UK.
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Tobin
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Leopold
authors.initials: L
authors.lastname: Eckhart
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: Erwin.Tschachler@meduniwien.ac.at.
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
mesh_terms: D019588:Aging, Premature / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000502:physiology; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; C502661:Atg7 protein, mouse; D008543:Melanins; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D000071193:Autophagy-Related Protein 7