title: Sharpin contributes to TNFα dependent NFκB activation and anti-apoptotic signalling in hepatocytes.
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.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sieber
authors.forename: Nicole
authors.initials: N
authors.lastname: Lange
authors.forename: Gwendlyn
authors.initials: G
authors.lastname: Kollmorgen
authors.forename: Annette
authors.initials: A
authors.lastname: Erhardt
authors.forename: Alexander
authors.initials: A
authors.lastname: Quaas
authors.forename: Arthur
authors.initials: A
authors.lastname: Gontarewicz
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sass
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Kreienkamp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D017093:Liver Failure / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; C425287:sharpin; C492590:Rnf31 protein, mouse; D044767:Ubiquitin-Protein Ligases