title: 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.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Zhigao
authors.initials: Z
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.forename: Fenghe
authors.initials: F
authors.lastname: Du
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D034281:Dynamins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009336:Necrosis / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D020033:Protein Isoforms; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C529563:PGAM5 protein, human; C570696:PGAM5 protein, mouse; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D034281:Dynamins