TY  - JOUR
A1  - Kumari, Snehlata
A1  - Redouane, Younes
A1  - Lopez-Mosqueda, Jaime
A1  - Shiraishi, Ryoko
A1  - Romanowska, Malgorzata
A1  - Lutzmayer, Stefan
A1  - Kuiper, Jan
A1  - Martinez, Conception
A1  - Đikić, Ivan
A1  - Pasparakis, Manolis
A1  - Ikeda, Fumiyo
T1  - Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis
T2  - eLife
N2  - 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.
KW  - LUBAC
KW  - Sharpin
KW  - TNFR1
KW  - apoptosis
KW  - cell biology
KW  - immunology
KW  - mouse
KW  - skin inflammation
KW  - ubiquitin
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/37797
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-377974
SN  - 2050-084X
N1  - Copyright © 2014, Kumari et al This article is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ , which permits unrestricted use and redistribution provided that the original author and source are credited.
VL  - 3
IS  - e03422
SP  - 1
EP  - 20
PB  - eLife Sciences Publications
CY  - Cambridge
ER  -