Universität zu Köln

Kumari, Snehlata, Redouane, Younes, Lopez-Mosqueda, Jaime, Shiraishi, Ryoko, Romanowska, Malgorzata, Lutzmayer, Stefan, Kuiper, Jan, Martinez, Conception, Dikic, Ivan ORCID: 0000-0001-8156-9511, Pasparakis, Manolis ORCID: 0000-0002-9870-0966 and Ikeda, Fumiyo ORCID: 0000-0003-0407-2768 (2014). Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis. eLife, 3. CAMBRIDGE: ELIFE SCIENCES PUBLICATIONS LTD. ISSN 2050-084X

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kumari, Snehlata UNSPECIFIED UNSPECIFIED UNSPECIFIED Redouane, Younes UNSPECIFIED UNSPECIFIED UNSPECIFIED Lopez-Mosqueda, Jaime UNSPECIFIED UNSPECIFIED UNSPECIFIED Shiraishi, Ryoko UNSPECIFIED UNSPECIFIED UNSPECIFIED Romanowska, Malgorzata UNSPECIFIED UNSPECIFIED UNSPECIFIED Lutzmayer, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuiper, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Martinez, Conception UNSPECIFIED UNSPECIFIED UNSPECIFIED Dikic, Ivan UNSPECIFIED orcid.org/0000-0001-8156-9511 UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Ikeda, Fumiyo UNSPECIFIED orcid.org/0000-0003-0407-2768 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-420984
DOI:	10.7554/eLife.03422
Journal or Publication Title:	eLife
Volume:	3
Date:	2014
Publisher:	ELIFE SCIENCES PUBLICATIONS LTD
Place of Publication:	CAMBRIDGE
ISSN:	2050-084X
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TUMOR-NECROSIS-FACTOR; KAPPA-B ACTIVATION; LINEAR UBIQUITIN CHAINS; TOLL-LIKE-RECEPTORS; POLYUBIQUITIN CHAINS; ASSEMBLY COMPLEX; STRUCTURAL BASIS; DEFICIENT MICE; TNF-ALPHA; IN-VIVO Multiple languages Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/42098