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

Lopez Posadas R, Becker C, Günther C, Tenzer S, Amann KU, Billmeier U, Atreya R, Fiorino G, Vetrano S, Danese S, Ekici AB, Wirtz S, Thonn V, Watson AJM, Brakebusch C, Bergo M, Neurath M, Atreya I (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 126

Pages Range: 4346-4360

Journal Issue: 11

DOI: 10.1172/JCI87545

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-? 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.

Authors with CRIS profile

Rocío Lopez Posadas Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Christoph Becker Professur für Molekulare Gastroenterologie Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Kerstin Ute Amann Department of Nephropathology Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Arif Bülent Ekici Institute of Human Genetics Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE) University of Gothenburg / Göteborgs universitet SE Sweden (SE) University of Copenhagen DK Denmark (DK) University of East Anglia GB United Kingdom (GB) Istituto Clinico Humanitas IT Italy (IT)

How to cite

APA:

Lopez Posadas, R., Becker, C., Günther, C., Tenzer, S., Amann, K.U., Billmeier, U.,... Atreya, I. (2016). The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis. Journal of Clinical Investigation, 126(11), 4346-4360. https://doi.org/10.1172/JCI87545

MLA:

Lopez Posadas, Rocío, et al. "The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis." Journal of Clinical Investigation 126.11 (2016): 4346-4360.

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