Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis
Snehlata Kumari,
Younes Redouane,
Jaime Lopez-Mosqueda,
Ryoko Shiraishi,
Malgorzata Romanowska,
Stefan Lutzmayer,
Jan Kuiper,
Conception Martinez,
Ivan Dikic,
Manolis Pasparakis,
Fumiyo Ikeda
Affiliations
Snehlata Kumari
Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
Younes Redouane
Institute of Molecular Biotechnology, Vienna, Austria
Jaime Lopez-Mosqueda
Institute of Biochemistry II, Goethe University Medical School, Frankfurt am Main, Germany
Ryoko Shiraishi
Institute of Molecular Biotechnology, Vienna, Austria
Malgorzata Romanowska
Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
Stefan Lutzmayer
Institute of Molecular Biotechnology, Vienna, Austria
Jan Kuiper
Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
Conception Martinez
Institute of Molecular Biotechnology, Vienna, Austria
Ivan Dikic
Institute of Biochemistry II, Goethe University Medical School, Frankfurt am Main, Germany
Manolis Pasparakis
Institute for Genetics, Center for Molecular Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
Fumiyo Ikeda
Institute of Molecular Biotechnology, Vienna, Austria
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.
