Rab2A is a pivotal switch protein that promotes either secretion or ER-associated degradation of (pro)insulin in insulin-secreting cells

Sci Rep. 2014 Nov 7;4:6952. doi: 10.1038/srep06952.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Biological Transport
  • COP-Coated Vesicles / metabolism
  • Cell Line, Tumor
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / ultrastructure
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum-Associated Degradation / genetics
  • Glucose / metabolism
  • Glucose / pharmacology*
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / genetics
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
  • Golgi Apparatus / drug effects*
  • Golgi Apparatus / metabolism
  • Golgi Apparatus / ultrastructure
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / ultrastructure
  • Mice
  • Polyubiquitin / genetics
  • Polyubiquitin / metabolism
  • Proinsulin / metabolism*
  • Protein Aggregates
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • rab GTP-Binding Proteins / antagonists & inhibitors
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Protein Aggregates
  • RNA, Small Interfering
  • Polyubiquitin
  • Proinsulin
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • Rab2a protein, mouse
  • rab GTP-Binding Proteins
  • Glucose