Journal article
N-terminal phosphorylation of protein phosphatase 2A/Bβ2 regulates translocation to mitochondria, dynamin-related protein 1 dephosphorylation, and neuronal survival
The FEBS journal, Vol.280(2), pp.662-673
01/2013
DOI: 10.1111/j.1742-4658.2012.08631.x
PMCID: PMC3549015
PMID: 22583914
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 translocation of Bβ2 can be attenuated by mutation of residues in close proximity to the catalytic site, but only if Ser20-Ser22 are available for phosphorylation, suggesting that PP2A/Bβ2 autodephosphorylation is necessary for OMM association, probably by uncovering the net positive charge of the mitochondrial targeting sequence. These results reveal another layer of complexity in the regulation of the mitochondrial fission-fusion equilibrium and its physiological and pathophysiological consequences in the nervous system.
Details
- Title: Subtitle
- N-terminal phosphorylation of protein phosphatase 2A/Bβ2 regulates translocation to mitochondria, dynamin-related protein 1 dephosphorylation, and neuronal survival
- Creators
- Ronald A Merrill - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAAndrew M SlupeStefan Strack
- Resource Type
- Journal article
- Publication Details
- The FEBS journal, Vol.280(2), pp.662-673
- Publisher
- England
- DOI
- 10.1111/j.1742-4658.2012.08631.x
- PMID
- 22583914
- PMCID
- PMC3549015
- ISSN
- 1742-464X
- eISSN
- 1742-4658
- Grant note
- T32 GM067795 / NIGMS NIH HHS NS077563 / NINDS NIH HHS NS057714 / NINDS NIH HHS R56 NS056244 / NINDS NIH HHS R01 NS043254 / NINDS NIH HHS T32 GM007337 / NIGMS NIH HHS F31 NS077563 / NINDS NIH HHS NS043254 / NINDS NIH HHS R01 NS057714 / NINDS NIH HHS R01 NS056244 / NINDS NIH HHS NS056244 / NINDS NIH HHS
- Language
- English
- Date published
- 01/2013
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984040373702771
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