Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells.
Rab2A, a small GTPase localizing to the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC), regulates COPI-dependent vesicular transport from the ERGIC. Rab2A knockdown inhibited glucose-stimulated insulin secretion and concomitantly enlarged the ERGIC in insulin-secreting cells. Large aggregates of polyubiquitinated proinsulin accumulated in the cytoplasmic vicinity of a unique large spheroidal ERGIC, designated the LUb-ERGIC. Well-known components of ER-associated degradation (ERAD) also accumulated at the LUb-ERGIC, creating a suitable site for ERAD-mediated protein quality control. Moreover, chronically high glucose levels, which induced the enlargement of the LUb-ERGIC and ubiquitinated protein aggregates, impaired Rab2A activity by promoting dissociation from its effector, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in response to poly (ADP-ribosyl)ation of GAPDH. The inactivation of Rab2A relieved glucose-induced ER stress and inhibited ER stress-induced apoptosis. Collectively, these results suggest that Rab2A is a pivotal switch that controls whether insulin should be secreted or degraded at the LUb-ERGIC and Rab2A inactivation ensures alleviation of ER stress and cell survival under chronic glucotoxicity.
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan.
Taichi
T
Sugawara
1] Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan [2] PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Fumi
F
Kano
Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan.
Masayuki
M
Murata
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D022181:COP-Coated Vesicles / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism; D011384:Proinsulin / Q000378:metabolism*; D066329:Protein Aggregates; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020693:rab2 GTP-Binding Protein
D005947:Glucose; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D025821:Polyubiquitin; D011384:Proinsulin; D066329:Protein Aggregates; D034741:RNA, Small Interfering; D020691:rab GTP-Binding Proteins; C000602046:Rab2a protein, mouse; D020693:rab2 GTP-Binding Protein