The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis
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
WEHI Research Division(s)
Cell Signalling And Cell Death
PubMed ID
27756058
Publisher's Version
https://doi.org/10.1172/JCI87545
NHMRC Grants
NHMRC/057905 NHMRC/1105754
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
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