Unbound MEDLINE

The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways.

Abstract

The programmed necrosis induced by TNF-α requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. We report the identification of RIP1- and RIP3-containing protein complexes that form specifically in response to necrosis induction. One component of these complexes is the mitochondrial protein phosphatase PGAM5, which presents as two splice variants, PGAM5L (long form) and PGAM5S (short form). Knockdown of either form attenuated necrosis induced by TNF-α as well as reactive oxygen species (ROS) and calcium ionophore, whereas knockdown of RIP3 and MLKL blocked only TNF-α-mediated necrosis. Upon necrosis induction, PGAM5S recruited the mitochondrial fission factor Drp1 and activated its GTPase activity by dephosphorylating the serine 637 site of Drp1. Drp1 activation caused mitochondrial fragmentation, an early and obligatory step for necrosis execution. These data defined PGAM5 as the convergent point for multiple necrosis pathways.

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  • Publisher Full Text
  • Authors

    Wang Z, Jiang H, Chen S, Du F, Wang X

    Source

    Cell 148:1-2 2012 Jan 20 pg 228-43

    MeSH

    Animals
    Apoptosis
    Carrier Proteins
    Dynamins
    HeLa Cells
    Humans
    Mice
    Mitochondria
    Mitochondrial Proteins
    Necrosis
    Phosphoric Monoester Hydrolases
    Protein Isoforms
    Receptor-Interacting Protein Serine-Threonine Kinases
    Signal Transduction

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22265414