TY - JOUR
T1 - The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways
AU - Wang, Zhigao
AU - Jiang, Hui
AU - Chen, She
AU - Du, Fenghe
AU - Wang, Xiaodong
N1 - Funding Information:
We would like to thank Drs. Steve McKnight, Joe Goldstein, and Mike Brown for support and encouragement; Dr. Ayako Suzuki for help with the 2D electrophoresis; Drs. Lai Wang, Agata Rybarska, and Gregory Kunkel for critical reading of the manuscript. This work was supported by the Howard Hughes Medical Institute and the National High Technology Projects 863 (2008AA022318) and 973 (2010CB835400) from Chinese Ministry of Science and Technology.
PY - 2012/1/20
Y1 - 2012/1/20
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2011.11.030
DO - 10.1016/j.cell.2011.11.030
M3 - Article
C2 - 22265414
AN - SCOPUS:84862909353
SN - 0092-8674
VL - 148
SP - 228
EP - 243
JO - Cell
JF - Cell
IS - 1-2
ER -