TY - JOUR
T1 - Rab32 modulates apoptosis onset and Mitochondria-associated Membrane (MAM) properties
AU - Bui, Michael
AU - Gilady, Susanna Y.
AU - Fitzsimmons, Ross E B
AU - Benson, Matthew D.
AU - Lynes, Emily M.
AU - Gesson, Kevin
AU - Alto, Neal M.
AU - Strack, Stefan
AU - Scott, John D.
AU - Simmen, Thomas
PY - 2010/10/8
Y1 - 2010/10/8
N2 - 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 ofPKAto 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.
AB - 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 ofPKAto 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.
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U2 - 10.1074/jbc.M110.101584
DO - 10.1074/jbc.M110.101584
M3 - Article
C2 - 20670942
AN - SCOPUS:77957790021
SN - 0021-9258
VL - 285
SP - 31590
EP - 31602
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 41
ER -