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

Günther, Claudia; He, Gui-Wei; Kremer, Andreas E.; Murphy, James M.; Petrie, Emma J.; Amann, Kerstin; Vandenabeele, Peter; Linkermann, Andreas; Poremba, Christopher; Schleicher, Ulrike; Dewitz, Christin; Krautwald, Stefan; Becker, Christoph; Wirtz, Stefan

doi:10.1172/jci87545

Cited by 130 publications

(170 citation statements)

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“…to plasma membrane; however, nec-1s did not prevent MLKL induction in response to ConA toxicity (13). At face value, nec1s protection in the ConA model suggests that RIPK1 kinase activity is required for MLK1-dependent cell death.…”

Section: What Pathway Killed the Hepatocyte?mentioning

confidence: 89%

“…The latter result is intriguing, as RIPK3, the only identified kinase capable of activating MLKL, is not detectable in normal hepatocytes (8,13). RIPK3 induction has been suggested to occur in chronic liver injury, such as alcoholic and nonalcoholic steatohepatitis; however, actual necroptosis due to putative induction of RIPK3 in the liver has not been convincingly demonstrated (14)(15)(16).…”

Section: What Pathway Killed the Hepatocyte?mentioning

confidence: 99%

“…Using Mlkl -/-mice and strain-matched controls, Günther et al clearly demonstrate a hepatocyte-intrinsic, RIPK3-independent role for MLKL in ConA-mediated liver injury (13). Mlkl -/-mice were marked- mice were resistant to ConA.…”

Section: What Pathway Killed the Hepatocyte?mentioning

confidence: 99%

“…It will also be important to determine if MLKL-mediated hepatocyte death is involved in other common liver diseases, such as alcoholic and nonalcoholic steatohepatitis, acute and chronic viral hepatitis, and idiosyncratic immune-mediated drug-induced liver injury. The study by Günther et al not only reveals that IFN-γ/STAT1 signaling induces MLKL, but also provides compelling evidence for a RIPK3-independent MLKL activation pathway, which might be referred to as noncanonical necroptosis (13). While the mechanism for MLKL induction is clearly defined, the mechanism(s) for phospho-activation of MLKL and the precise role of RIPK1 in this form of necroptosis will require additional work.…”

Section: 7mentioning

confidence: 99%

“…Günther et al also explored the possibility that their findings in the mouse ConA immune-mediated toxicity model are relevant to human autoimmune hepatitis (AIH), which is characterized by an influx of adaptive immune cells (lymphocytes and plasma cells) in the liver and extensive hepatocyte death (13). Indeed, immunohistochemistry of liver sections from patients with AIH revealed increased pMLKL expression and plasma membrane localization.…”

Section: Outstanding Questionsmentioning

confidence: 99%

See 4 more Smart Citations

A murder mystery in the liver: who done it and how?

Dara¹,

Liu²,

Kaplowitz³

2016

Journal of Clinical Investigation

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Section: What Pathway Killed the Hepatocyte?mentioning

confidence: 89%

Section: What Pathway Killed the Hepatocyte?mentioning

confidence: 99%

Section: What Pathway Killed the Hepatocyte?mentioning

confidence: 99%

Section: 7mentioning

confidence: 99%

Section: Outstanding Questionsmentioning

confidence: 99%

See 3 more Smart Citations

A murder mystery in the liver: who done it and how?

Dara¹,

Liu²,

Kaplowitz³

2016

Journal of Clinical Investigation

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Macrophage‐derived MLKL in alcohol‐associated liver disease: Regulation of phagocytosis

Fan

McMullen

et al. 2023

Hepatology

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Background and Aims: Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3) −/− mice are completely protected from ethanol-induced liver injury, Mlkl −/− mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury.Approach and Results: Bone marrow transplants between Mlkl −/− mice and littermates were conducted to distinguish the role of myeloid versus nonmyeloid

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Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

et al. 2019

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Cell death is a natural process for the turnover of aged cells, but it can also arise as a result of pathological conditions. Cell death is recognized as a key feature in both acute and chronic hepatobiliary diseases caused by drug, alcohol, and fat uptake; by viral infection; or after surgical intervention. In the case of chronic disease, cell death can lead to (chronic) secondary inflammation, cirrhosis, and the progression to liver cancer. In liver transplantation, graft preservation and ischemia/reperfusion injury are associated with acute cell death. In both cases, so‐called programmed cell death modalities are involved. Several distinct types of programmed cell death have been described of which apoptosis and necroptosis are the most well known. Parenchymal liver cells, including hepatocytes and cholangiocytes, are susceptible to both apoptosis and necroptosis, which are triggered by distinct signal transduction pathways. Apoptosis is dependent on a proteolytic cascade of caspase enzymes, whereas necroptosis induction is caspase‐independent. Moreover, different from the “silent” apoptotic cell death, necroptosis can cause a secondary inflammatory cascade, so‐called necroinflammation, triggered by the release of various damage‐associated molecular patterns (DAMPs). These DAMPs activate the innate immune system, leading to both local and systemic inflammatory responses, which can even cause remote organ failure. Therapeutic targeting of necroptosis by pharmacological inhibitors, such as necrostatin‐1, shows variable effects in different disease models.

show abstract

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

Cited by 130 publications

References 60 publications

A murder mystery in the liver: who done it and how?

A murder mystery in the liver: who done it and how?

Macrophage‐derived MLKL in alcohol‐associated liver disease: Regulation of phagocytosis

Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

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