| First Author | Sieber S | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 1 | Pages | e29993 |
| PubMed ID | 22253853 | Mgi Jnum | J:184313 |
| Mgi Id | MGI:5320709 | Doi | 10.1371/journal.pone.0029993 |
| Citation | Sieber S, et al. (2012) Sharpin contributes to TNFalpha dependent NFkappaB activation and anti-apoptotic signalling in hepatocytes. PLoS One 7(1):e29993 |
| abstractText | TNFalpha stimulates both pro- and anti-apoptotic signalling in hepatocytes. Anti-apoptotic signalling depends on a cascade of ubiquitylation steps leading to NFkappaB 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 TNFalpha even in the absence of transcriptional inhibition. TNFalpha induced activation of NFkappaB was strongly reduced in hepatocytes from Sharpin-deficient mice, due to reduced and delayed phosphorylation and degradation of IkappaBalpha. Injection of TNFalpha-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, NFkappaB activation, and protection of the liver against inflammatory damaging signals. |
