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- Title
The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis.
- Authors
Günther, Claudia; Gui-Wei He; Kremer, Andreas E.; Murphy, James M.; Petrie, Emma J.; Amann, Kerstin; Vandenabeele, Peter; Linkermann, Andreas; Poremba, Christopher; Schleicher, Ulrike; Dewitz, Christin; Krautwald, Stefan; Neurath, Markus F.; Becker, Christoph; Wirtz, Stefan; He, Gui-Wei
- 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-γ 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.
- Subjects
NECROSIS; CELL death; CHRONIC active hepatitis; TRANSCRIPTION factors; LIVER diseases; PROTEIN metabolism; ANIMALS; CARRIER proteins; EPITHELIAL cells; INTERFERONS; MICE; PROTEIN kinases; PROTEINS
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 11, p4346
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI87545