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 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.

Download full text files

Export metadata

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 ĐikićORCiDGND, Manolis Pasparakis, Fumiyo Ikeda
URN:urn:nbn:de:hebis:30:3-377974
DOI:https://doi.org/10.7554/eLife.03422
ISSN:2050-084X
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/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
Page Number: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 / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0