The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis

Gunther, C; He, GW; Kremer, AE; Murphy, JM; Petrie, EJ; Amann, K; Vandenabeele, P; Linkermann, A; Poremba, C; Schleicher, U; Dewitz, C; Krautwald, S; Neurath, MF; Becker, C; Wirtz, S

Author(s): Gunther, C; He, GW; Kremer, AE; Murphy, JM; Petrie, EJ; Amann, K; Vandenabeele, P; Linkermann, A; Poremba, C; Schleicher, U; Dewitz, C; Krautwald, S; Neurath, MF; Becker, C; Wirtz, S;
Details: Publication Year 2016-10-18,Volume 126,Issue #11,Page 4346-4360
Journal Title: J Clin Invest
Publication Type: Journal Article
Abstract: Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor-interacting protein (RIP) kinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-gamma in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases.
Publisher: Am Assoc Clin Sci
Research Division(s): Cell Signalling And Cell Death
PubMed ID: 27756058
Link To PubMed Central Version: https://www-ncbi-nlm-nih-gov/pmc/articles/PMC5096909/
Publisher's Version: https://doi.org/10.1172/JCI87545
NHMRC Grants: NHMRC/057905, NHMRC/1105754,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-10-21 05:05:52

Last Modified: 2018-01-10 09:27:32