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PLoS One. 2012;7(1):e29993. doi: 10.1371/journal.pone.0029993. Epub 2012 Jan 9.

Sharpin contributes to TNFα dependent NFκB activation and anti-apoptotic signalling in hepatocytes.

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1
Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Abstract

TNFα stimulates both pro- and anti-apoptotic signalling in hepatocytes. Anti-apoptotic signalling depends on a cascade of ubiquitylation steps leading to NFκB activation. Using Sharpin-deficient mice, we show that the ubiquitin binding protein Sharpin interacts with Hoip, an E3 ligase which generates linear ubiquitin chains. Sharpin-deficiency sensitized hepatocytes to induction of apoptosis by TNFα even in the absence of transcriptional inhibition. TNFα induced activation of NFκB was strongly reduced in hepatocytes from Sharpin-deficient mice, due to reduced and delayed phosphorylation and degradation of IκBα. Injection of TNFα-inducing lipopolysaccharides led to strongly exacerbated liver damage and premature death in Sharpin-deficient mice. Our findings point to an essential role of Sharpin in linear ubiquitin chain formation, NFκB activation, and protection of the liver against inflammatory damaging signals.

PMID:
22253853
PMCID:
PMC3253811
DOI:
10.1371/journal.pone.0029993
[Indexed for MEDLINE]
Free PMC Article
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