Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase

Liming Sun, Huayi Wang, Zhigao Wang, Sudan He, She Chen, Daohong Liao, Lai Wang, Jiacong Yan, Weilong Liu, Xiaoguang Lei, Xiaodong Wang

Research output: Contribution to journalArticle

1037 Scopus citations

Abstract

The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl) acrylamide - hereafter referred to as necrosulfonamide - that specifically blocks necrosis downstream of RIP3 activation. An affinity probe derived from necrosulfonamide and coimmunoprecipitation using anti-RIP3 antibodies both identified the mixed lineage kinase domain-like protein (MLKL) as the interacting target. MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.

Original languageEnglish (US)
Pages (from-to)213-227
Number of pages15
JournalCell
Volume148
Issue number1-2
DOIs
StatePublished - Jan 20 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X., & Wang, X. (2012). Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell, 148(1-2), 213-227. https://doi.org/10.1016/j.cell.2011.11.031