Rab32 Modulates Apoptosis Onset and Mitochondria-associated Membrane (MAM) Properties

被引:135
作者
Bui, Michael
Gilady, Susanna Y.
Fitzsimmons, Ross E. B.
Benson, Matthew D.
Lynes, Emily M.
Gesson, Kevin
Alto, Neal M. [2 ]
Strack, Stefan [4 ]
Scott, John D. [3 ]
Simmen, Thomas [1 ]
机构
[1] Univ Alberta, Fac Med & Dent, Dept Cell Biol, Sch Mol & Syst Med, Edmonton, AB T6G 2H7, Canada
[2] Univ Texas SW, Dept Microbiol, Dallas, TX 75390 USA
[3] Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98195 USA
[4] Univ Iowa, Dept Pharmacol, Carver Coll Med, Iowa City, IA 52242 USA
基金
加拿大自然科学与工程研究理事会; 美国国家卫生研究院;
关键词
DEPENDENT PROTEIN-KINASE; TRAIL-INDUCED APOPTOSIS; ENDOPLASMIC-RETICULUM; OXIDATIVE-METABOLISM; CA2+ CONCENTRATION; IN-VITRO; PHOSPHORYLATION; CALCIUM; COMPLEX; CAMP;
D O I
10.1074/jbc.M110.101584
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:31590 / 31602
页数:13
相关论文
共 60 条
[1]   Essential role of A-kinase anchor protein 121 for cAMP signaling to mitochondria [J].
Affaitati, A ;
Cardone, L ;
de Cristofaro, T ;
Carlucci, A ;
Ginsberg, MD ;
Varrone, S ;
Gottesman, ME ;
Avvedimento, EV ;
Feliciello, A .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (06) :4286-4294
[2]   Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics [J].
Alto, NM ;
Soderling, J ;
Scott, JD .
JOURNAL OF CELL BIOLOGY, 2002, 158 (04) :659-668
[3]   Akt and 14-3-3 Control a PACS-2 Homeostatic Switch that Integrates Membrane Traffic with TRAIL-Induced Apoptosis [J].
Aslan, Joseph E. ;
You, Huihong ;
Williamson, Danielle M. ;
Endig, Jessica ;
Youker, Robert T. ;
Thomas, Laurel ;
Shu, Hongjun ;
Du, Yuhong ;
Milewski, Robert L. ;
Brush, Matthew H. ;
Possemato, Anthony ;
Sprott, Kam ;
Fu, Haian ;
Greis, Kenneth D. ;
Runckel, Douglas N. ;
Vogel, Arndt ;
Thomas, Gary .
MOLECULAR CELL, 2009, 34 (04) :497-509
[4]   A role for Rab5 in structuring the endoplasmic reticulum [J].
Audhya, Anion ;
Desai, Arshad ;
Oegema, Karen .
JOURNAL OF CELL BIOLOGY, 2007, 178 (01) :43-56
[5]   Molecular cloning, bacterial expression and properties of Rab31 and Rab32 - New blood platelet Rab proteins [J].
Bao, XK ;
Faris, AE ;
Jang, EK ;
Haslam, RJ .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 2002, 269 (01) :259-271
[6]   A-kinase anchoring proteins take shape [J].
Beene, Darren L. ;
Scott, John D. .
CURRENT OPINION IN CELL BIOLOGY, 2007, 19 (02) :192-198
[7]   Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis [J].
Boehning, D ;
Patterson, RL ;
Sedaghat, L ;
Glebova, NO ;
Kurosaki, T ;
Snyder, SH .
NATURE CELL BIOLOGY, 2003, 5 (12) :1051-1061
[8]   A protein complex containing Mdm10p, Mdm12p, and Mmm1p links mitochondrial membranes and DNA to cytoskeleton-based segregation machinery [J].
Boldogh, IR ;
Nowakowski, DW ;
Yang, HC ;
Chung, HS ;
Karmon, S ;
Royes, P ;
Pon, LA .
MOLECULAR BIOLOGY OF THE CELL, 2003, 14 (11) :4618-4627
[9]   Calcium dynamics and endoplasmic reticular function in the regulation of protein synthesis: implications for cell growth and adaptability [J].
Brostrom, MA ;
Brostrom, CO .
CELL CALCIUM, 2003, 34 (4-5) :345-363
[10]   Control of mitochondria dynamics and oxidative metabolism by cAMP, AKAPs and the proteasome [J].
Carlucci, Annalisa ;
Lignitto, Luca ;
Feliciello, Antonio .
TRENDS IN CELL BIOLOGY, 2008, 18 (12) :604-613