Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells
SCIENTIFIC REPORTS
Authors: Sugawara, Taichi; Kano, Fumi; Murata, Masayuki
Abstract
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.
Comprehensive analysis of the value of RAB family genes in prognosis of breast invasive carcinoma
BIOSCIENCE REPORTS
Authors: Lin, Shitong; Cao, Canhui; Meng, Yifan; Wu, Ping; Gao, Peipei; Zhi, Wenhua; Peng, Ting; Wu, Peng; Gui, Lingli
Abstract
Purpose: Several RAB family genes have been studied extensively and proven to play pivotal roles in the occurrence and development of certain cancers. Here, we explored commonly expressed RAB family genes in humans and their prognostic significance using bioinformatics, and then identified potential biomarkers of breast invasive carcinoma (BRCA). Materials and methods: The prognostic values (overall survival) of RAB family genes in BRCA were obtained using Gene Expression Profiling Interactive Analysis (GEPIA). The expression patterns of RAB family genes and their relationships with clinicopathological parameters in BRCA were measured using the ONCOMINE and UALCAN databases, respectively. Genetic mutations and survival analysis were investigated using the cBio Cancer Genomics Portal (c-BioPortal). Interacting genes of potential biomarkers were identified using STRING, and functional enrichment analyses were performed using FunRich v3.1.3. Results: In total, 64 RAB genes were identified and analyzed in our study. Results showed that RAB1B, RAB2A, and RAB18 were up-regulated and significantly associated with poor overall survival in BRCA. Furthermore, their higher expression was positively correlated with clinicopathological parameters (e.g. cancer stage and nodal metastasis status). DNA copy number amplifications and mRNA up-regulationwere the main genetic mutations, and the altered group showed significantly poorer overall survival compared with the unaltered group. Functional enrichment analysis of RAB1B, RAB2A, and RAB18 indicated they were closely involved in GTPase activity. Conclusions: RAB1B, RAB2A, and RAB18 were up-regulated and significantly correlated with poor prognosis in BRCA. Thus, they could be applied as novel biomarkers of BRCA in future studies.