title: Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis.
abstract: Linear Ubiquitin chain Assembly Complex (LUBAC) is an E3 ligase complex that generates linear ubiquitin chains and is important for tumour necrosis factor (TNF) signaling activation. Mice lacking Sharpin, a critical subunit of LUBAC, spontaneously develop inflammatory lesions in the skin and other organs. Here we show that TNF receptor 1 (TNFR1)-associated death domain (TRADD)-dependent TNFR1 signaling in epidermal keratinocytes drives skin inflammation in Sharpin-deficient mice. Epidermis-restricted ablation of Fas-associated protein with death domain (FADD) combined with receptor-interacting protein kinase 3 (RIPK3) deficiency fully prevented skin inflammation, while single RIPK3 deficiency only delayed and partly ameliorated lesion development in Sharpin-deficient mice, showing that inflammation is primarily driven by TRADD- and FADD-dependent keratinocyte apoptosis while necroptosis plays a minor role. At the cellular level, Sharpin deficiency sensitized primary murine keratinocytes, human keratinocytes, and mouse embryonic fibroblasts to TNF-induced apoptosis. Depletion of FADD or TRADD in Sharpin-deficient HaCaT cells suppressed TNF-induced apoptosis, indicating the importance of FADD and TRADD in Sharpin-dependent anti-apoptosis signaling in keratinocytes.
authors.affiliation: Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Snehlata
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Institute of Molecular Biotechnology, Vienna, Austria.
authors.forename: Younes
authors.initials: Y
authors.lastname: Redouane
authors.affiliation: Institute of Biochemistry II, Goethe University Medical School, Frankfurt am Main, Germany.
authors.forename: Jaime
authors.initials: J
authors.lastname: Lopez-Mosqueda
authors.affiliation: Institute of Molecular Biotechnology, Vienna, Austria.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Shiraishi
authors.affiliation: Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Romanowska
authors.affiliation: Institute of Molecular Biotechnology, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lutzmayer
authors.affiliation: Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Institute of Molecular Biotechnology, Vienna, Austria.
authors.forename: Conception
authors.initials: C
authors.lastname: Martinez
authors.affiliation: Institute of Biochemistry II, Goethe University Medical School, Frankfurt am Main, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.affiliation: Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Institute of Molecular Biotechnology, Vienna, Austria.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D010641:Phenotype; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology*; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D053200:Fas-Associated Death Domain Protein; D009419:Nerve Tissue Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D053199:TNF Receptor-Associated Death Domain Protein; D014409:Tumor Necrosis Factor-alpha; C425287:sharpin; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse
keywords: LUBAC; Sharpin; TNFR1; apoptosis; cell biology; immunology; mouse; skin inflammation; ubiquitin