Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties

Michael Bui; Susanna Y Gilady; Ross E B Fitzsimmons; Matthew D Benson; Emily M Lynes; Kevin Gesson; Neal M Alto; Stefan Strack; John D Scott; Thomas Simmen

doi:10.1074/jbc.M110.101584

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Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties

Journal article

Open access

Peer reviewed

Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties

Michael Bui, Susanna Y Gilady, Ross E B Fitzsimmons, Matthew D Benson, Emily M Lynes, Kevin Gesson, Neal M Alto, Stefan Strack, John D Scott and Thomas Simmen

The Journal of biological chemistry, Vol.285(41), pp.31590-31602

10/08/2010

DOI: 10.1074/jbc.M110.101584

PMCID: PMC2951233

PMID: 20670942

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Abstract

The mitochondria-associated membrane (MAM) has emerged as an endoplasmic reticulum (ER) signaling hub that accommodates ER chaperones, including the lectin calnexin. At the MAM, these chaperones control ER homeostasis but also play a role in the onset of ER stress-mediated apoptosis, likely through the modulation of ER calcium signaling. These opposing roles of MAM-localized chaperones suggest the existence of mechanisms that regulate the composition and the properties of ER membrane domains. Our results now show that the GTPase Rab32 localizes to the ER and mitochondria, and we identify this protein as a regulator of MAM properties. Consistent with such a role, Rab32 modulates ER calcium handling and disrupts the specific enrichment of calnexin on the MAM, while not affecting the ER distribution of protein-disulfide isomerase and mitofusin-2. Furthermore, Rab32 determines the targeting of PKA to mitochondrial and ER membranes and through its overexpression or inactivation increases the phosphorylation of Bad and of Drp1. Through a combination of its functions as a PKA-anchoring protein and a regulator of MAM properties, the activity and expression level of Rab32 determine the speed of apoptosis onset.

GTP Phosphohydrolases

Molecular Chaperones - metabolism

Calcium - metabolism

Protein Disulfide-Isomerases - metabolism

Humans

Endoplasmic Reticulum - metabolism

rab GTP-Binding Proteins - genetics

Mitochondrial Proteins - genetics

Calnexin - genetics

Cyclic AMP-Dependent Protein Kinases - genetics

Mitochondria - genetics

Mitochondrial Proteins - metabolism

Membrane Proteins - metabolism

Calnexin - metabolism

Cyclic AMP-Dependent Protein Kinases - metabolism

rab GTP-Binding Proteins - metabolism

Endoplasmic Reticulum - genetics

Membrane Proteins - genetics

Molecular Chaperones - genetics

Mitochondria - metabolism

Protein Disulfide-Isomerases - genetics

Apoptosis - physiology

HeLa Cells

Unfolded Protein Response - physiology

Intracellular Membranes - metabolism

Details

Title: Subtitle: Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties
Creators: Michael Bui - Department of Cell Biology, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
Susanna Y Gilady
Ross E B Fitzsimmons
Matthew D Benson
Emily M Lynes
Kevin Gesson
Neal M Alto
Stefan Strack
John D Scott
Thomas Simmen
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.285(41), pp.31590-31602
DOI: 10.1074/jbc.M110.101584
PMID: 20670942
PMCID: PMC2951233
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: NS057714 / NINDS NIH HHS R56 NS056244 / NINDS NIH HHS R01 NS043254 / NINDS NIH HHS P01 DK054441 / NIDDK NIH HHS R01 DK54441 / NIDDK NIH HHS R01 NS057714 / NINDS NIH HHS R01 NS056244 / NINDS NIH HHS NS056244 / NINDS NIH HHS
Language: English
Date published: 10/08/2010
Academic Unit: Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040445702771

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