title: Autophagy deficient melanocytes display a senescence associated secretory phenotype that includes oxidized lipid mediators.
abstract: Autophagy is a recycling program which allows cells to adapt to metabolic needs and to stress. Defects in autophagy can affect metabolism, aging, proteostasis and inflammation. Autophagy pathway genes, including autophagy related 7 (Atg7), have been associated with the regulation of skin pigmentation, and autophagy defects disturb the biogenesis and transport of melanosomes in melanocytes as well as transfer and processing of melanin into keratinocytes. We have previously shown that mice whose melanocytes or keratinocytes lack Atg7 (and thus autophagy) as a result of specific gene knockout still retained functioning melanosome synthesis and transfer, and displayed only moderate reduction of pigmentation. In cell culture the Atg7 deficient melanocytes were prone to premature senescence and dysregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling. To elucidate the biochemical basis of this phenotype, we performed a study on global gene expression, protein secretion and phospholipid composition in Atg7 deficient versus Atg7 expressing melanocytes. In cell culture Atg7 deficient melanocytes showed a pro-inflammatory gene expression signature and secreted higher levels of C-X-C motif chemokine ligand -1,-2,-10 and -12 (Cxcl1, Cxcl2, Cxcl10, Cxcl12), which are implicated in the pathogenesis of pigmentary disorders and expressed higher amounts of matrix metalloproteinases -3 and -13 (Mmp3, Mmp13). The analysis of membrane phospholipid composition identified an increase in the arachidonic- to linoleic acid ratio in the autophagy deficient cells, as well as an increase in oxidized phospholipid species that act as danger associated molecular patterns (DAMPs). The secretion of inflammation related factors suggests that autophagy deficient melanocytes display a senescence associated secretory phenotype (SASP), and we propose oxidized lipid mediators as novel components of this SASP.
authors.affiliation: Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria; Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Chunya
authors.initials: C
authors.lastname: Ni
authors.affiliation: Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria; Christian Doppler Laboratory for the Biotechnology of Skin Aging, Vienna, Austria.
authors.forename: Marie-Sophie
authors.initials: MS
authors.lastname: Narzt
authors.affiliation: Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria; Christian Doppler Laboratory for the Biotechnology of Skin Aging, Vienna, Austria.
authors.forename: Ionela-Mariana
authors.initials: IM
authors.lastname: Nagelreiter
authors.affiliation: Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria; Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Cheng Feng
authors.initials: CF
authors.lastname: Zhang
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: Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria.
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Rossiter
authors.affiliation: Christian Doppler Laboratory for the Biotechnology of Skin Aging, Vienna, Austria; Department of Biotechnology, BOKU-VIBT University of Natural Resources and Life Sciences Vienna, Muthgasse 18, 1190 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
authors.affiliation: Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria.
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
authors.affiliation: Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria; Christian Doppler Laboratory for the Biotechnology of Skin Aging, Vienna, Austria. Electronic address: florian.gruber@meduniwien.ac.at.
authors.forename: Florian
authors.initials: F
authors.lastname: Gruber
mesh_terms: D000375:Aging; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071193:Autophagy-Related Protein 7 / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: C502661:Atg7 protein, mouse; D008055:Lipids; D000071193:Autophagy-Related Protein 7
keywords: Autophagy; DAMP; Oxidized lipids; SASP; Senescence