Editors' ChoiceCell death

Parkin protects against necroptosis

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Science Signaling  20 Aug 2019:
Vol. 12, Issue 595, eaaz1464
DOI: 10.1126/scisignal.aaz1464

Activation of Parkin by AMPK-mediated phosphorylation inhibits RIPK3 and prevents necroptosis.

Necroptosis is a regulated form of cell death that leads to inflammation and cancer. The sequential activation of the kinase RIPK1 and the related kinase RIPK3 leads to the RIPK3-mediated phosphorylation of the pseudokinase MLKL, which oligomerizes and permeabilizes the cell membrane. Noting that loss of the E3 ubiquitin ligase Parkin is associated with increased inflammation and tumor formation in mouse models of neurodegenerative disease and cancer, Lee et al. investigated the role of Parkin in regulating necroptosis. In cells, Parkin interacted with RIPK3 and promoted its polyubiquitylation, resulting in decreased phosphorylation of MLKL. The polyubiquitylation of RIPK3 required that the kinase AMPK phosphorylate Ser9 in Parkin to activate its E3 ubiquitin ligase activity. Polyubiquitylation of RIPK3 was decreased in cells expressing Parkin with colon cancer–associated mutations that abolished the interaction of Parkin with RIPK3 or with a mutation that prevented AMPK-mediated phosphorylation. Parkin-deficient mice showed increased inflammation and enhanced phosphorylation of RIPK3 in the small intestine and spontaneously developed intestinal polyps at a higher rate than did control mice, effects that were reduced by treatment with a RIPK3 inhibitor. In a model of colitis-associated cancer, pharmacological activation of AMPK reduced inflammation, polyp formation, and RIPK3 phosphorylation in wild-type mice but not in Parkin-deficient mice. The authors speculate that the activation of AMPK in necroptotic cells may be triggered by low ATP concentrations, but as Cao and Tait note in the associated commentary, it remains to be determined why a pathway to inhibit necroptosis would be activated at the same time as the necroptosis pathway itself.

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