Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells.
Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells.
复制标题
Rab2A 是一种关键开关蛋白，可促进胰岛素分泌细胞中胰岛素（原）的分泌或 ER 相关的降解。
DOI：
10.1038/srep06952
复制
发表时间：
2014-11-07
影响因子：
4.6
通讯作者：
Murata M
中科院分区：
文献类型：
--
作者：
Sugawara T;Kano F;Murata M
Rab2a是一个定位于内质网(ER)-高尔基体中间室(ERGIC)的小GTP酶，它调节依赖COPI的囊泡从ERGIC转运。Rab2a基因敲除抑制了葡萄糖刺激的胰岛素分泌，同时扩大了胰岛素分泌细胞的ERGIC。多泛素化的胰岛素原聚集在一个独特的大球状ERGIC的细胞质附近，称为Lub-ERGIC。众所周知的内质网相关降解成分(ERAD)也在Lub-ERGIC积累，为ERAD介导的蛋白质质量控制创造了合适的位置。此外，长期高糖水平导致Lub-ERGIC和泛素化蛋白聚集体的扩大，通过促进其效应物3-磷酸甘油醛脱氢酶(GAPDH)的解离而削弱GAPDH的活性，以响应GAPDH的聚合(ADP-核糖基)。Rab2A的失活减轻了葡萄糖诱导的内质网应激，抑制了内质网应激诱导的细胞凋亡。综上所述，这些结果表明，Rab2A是控制胰岛素在Lub-ERGIC分泌还是降解的关键开关，而Rab2A的失活确保了内质网应激的缓解和细胞在慢性糖毒性下的存活。
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.