Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase - PubMed (original) (raw)
. 2012 Jan 20;148(1-2):213-27.
doi: 10.1016/j.cell.2011.11.031.
Affiliations
- PMID: 22265413
- DOI: 10.1016/j.cell.2011.11.031
Free article
Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase
Liming Sun et al. Cell. 2012.
Free article
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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Comment in
- RIP3 finds partners in crime.
Chan FK, Baehrecke EH. Chan FK, et al. Cell. 2012 Jan 20;148(1-2):17-8. doi: 10.1016/j.cell.2011.12.020. Cell. 2012. PMID: 22265396 Free PMC article. - Cell death: Programmed necrosis: putting the pieces together.
Papatriantafyllou M. Papatriantafyllou M. Nat Rev Mol Cell Biol. 2012 Feb 8;13(3):135. doi: 10.1038/nrm3292. Nat Rev Mol Cell Biol. 2012. PMID: 22314401 No abstract available.
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