N-terminal phosphorylation of protein phosphatase 2A/Bβ2 regulates translocation to mitochondria, dynamin-related protein 1 dephosphorylation, and neuronal survival.

The FEBS Journal
Ronald A MerrillStefan Strack

Abstract

The neuron-specific Bβ2 regulatory subunit of protein phosphatase 2A (PP2A), a product of the spinocerebellar ataxia type 12 disease gene PPP2R2B, recruits heterotrimeric PP2A to the outer mitochondrial membrane (OMM) through its N-terminal mitochondrial targeting sequence. OMM-localized PP2A/Bβ2 induces mitochondrial fragmentation, thereby increasing susceptibility to neuronal insults. Here, we report that PP2A/Bβ2 activates the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) by dephosphorylating Ser656, a highly conserved inhibitory phosphorylation site targeted by the neuroprotective protein kinase A-A kinase anchoring protein 1 complex. We further show that translocation of PP2A/Bβ2 to mitochondria is regulated by phosphorylation of Bβ2 at three N-terminal serines. Phosphomimetic substitution of Ser20, Ser21, and Ser22 renders Bβ2 cytosolic, blocks Drp1 dephosphorylation and mitochondrial fragmentation, and abolishes the ability of Bβ2 overexpression to induce apoptosis in cultured hippocampal neurons. Alanine substitution of Ser20-Ser22 to prevent phosphorylation has the opposite effect, promoting association of Bβ2 with mitochondria, Drp1 dephosphorylation, mitochondrial fission, and neuronal death. OMM tran...Continue Reading

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Citations

Feb 26, 2016·Critical Reviews in Biochemistry and Molecular Biology·Nathan Wlodarchak, Yongna Xing
Oct 22, 2016·Cellular and Molecular Neurobiology·Dah Ihm KimHo Jae Han
Jan 19, 2017·International Journal of Molecular Sciences·Chenxia HuLanjuan Li
Feb 6, 2017·Journal of Cell Science·Kyle H Flippo, Stefan Strack
Aug 5, 2016·American Journal of Physiology. Renal Physiology·Huiwen RenJanet D Klein
Sep 30, 2018·Antioxidants & Redox Signaling·Elianne P BulthuisWerner J H Koopman
Feb 14, 2019·American Journal of Physiology. Cell Physiology·Stephanie M AdaniyaBong Sook Jhun
Feb 20, 2020·Nature Reviews. Molecular Cell Biology·Marta GiacomelloLuca Scorrano
Nov 3, 2016·Current Opinion in Neurology·Rachael L Cohen, Russell L Margolis
Feb 2, 2021·Frontiers in Cellular and Infection Microbiology·Fushan GaoMary X D O'Riordan

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