title: Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties.
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.
authors.affiliation: Department of Cell Biology, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Bui
authors.forename: Susanna Y
authors.initials: SY
authors.lastname: Gilady
authors.forename: Ross E B
authors.initials: RE
authors.lastname: Fitzsimmons
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Benson
authors.forename: Emily M
authors.initials: EM
authors.lastname: Lynes
authors.forename: Kevin
authors.initials: K
authors.lastname: Gesson
authors.forename: Neal M
authors.initials: NM
authors.lastname: Alto
authors.forename: Stefan
authors.initials: S
authors.lastname: Strack
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.forename: Thomas
authors.initials: T
authors.lastname: Simmen
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D037281:Calnexin / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D037281:Calnexin; D017868:Cyclic AMP-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C466094:Rab32 protein, human; D020691:rab GTP-Binding Proteins; D019704:Protein Disulfide-Isomerases; D002118:Calcium