Cell
Volume 148, Issues 1–2, 20 January 2012, Pages 228-243
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Article
The Mitochondrial Phosphatase PGAM5 Functions at the Convergence Point of Multiple Necrotic Death Pathways

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Summary

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.

Highlights

► PGAM5 is a mitochondrial phosphatase that functions in programmed necrosis (necroptosis) ► Both splicing variants of PGAM5, PGAM5L and PGAM5S, are required for necroptosis ► PGAM5 dephosphorylates and activates mitochondrial fission protein Drp1 ► PGAM5 is required for necrosis induced by TNF-α, ROS, and calcium overload

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