Sharpin prevents skin inflammation by inhibiting TNFR1-induced keratinocyte apoptosis

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 subu
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.
show moreshow less

Download full text files

Export metadata

  • Export Bibtex
  • Export RIS

Additional Services

    Share in Twitter Search Google Scholar
Metadaten
Author:Snehlata Kumari, Younes Redouane, Jaime Lopez-Mosqueda, Ryoko Shiraishi, Malgorzata Romanowska, Stefan Lutzmayer, Jan Kuiper, Conception Martinez, Ivan Dikic, Manolis Pasparakis, Fumiyo Ikeda
URN:urn:nbn:de:hebis:30:3-377974
DOI:http://dx.doi.org/10.7554/eLife.03422
ISSN:2050-084X
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25443631
Parent Title (English):eLife
Publisher:eLife Sciences Publications
Place of publication:Cambridge
Document Type:Article
Language:English
Date of Publication (online):2014/12/02
Date of first Publication:2014/12/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2015/07/23
Tag:LUBAC; Sharpin; TNFR1; apoptosis; cell biology; immunology; mouse; skin inflammation; ubiquitin
Volume:3
Issue:e03422
Pagenumber:20
First Page:1
Last Page:20
Note:
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.
HeBIS PPN:369743393
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

$Rev: 11761 $