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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. Larg...

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Autores principales: Sugawara, Taichi, Kano, Fumi, Murata, Masayuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381769/
https://www.ncbi.nlm.nih.gov/pubmed/25377857
http://dx.doi.org/10.1038/srep06952
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author Sugawara, Taichi
Kano, Fumi
Murata, Masayuki
author_facet Sugawara, Taichi
Kano, Fumi
Murata, Masayuki
author_sort Sugawara, Taichi
collection PubMed
description 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.
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spelling pubmed-53817692017-04-11 Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells Sugawara, Taichi Kano, Fumi Murata, Masayuki Sci Rep Article 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. Nature Publishing Group 2014-11-07 /pmc/articles/PMC5381769/ /pubmed/25377857 http://dx.doi.org/10.1038/srep06952 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Article
Sugawara, Taichi
Kano, Fumi
Murata, Masayuki
Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells
title Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells
title_full Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells
title_fullStr Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells
title_full_unstemmed Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells
title_short Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells
title_sort rab2a is a pivotal switch protein that promotes either secretion or er-associated degradation of (pro)insulin in insulin-secreting cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381769/
https://www.ncbi.nlm.nih.gov/pubmed/25377857
http://dx.doi.org/10.1038/srep06952
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