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A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1 Activation in Pancreatic β Cells
Yifu Qiu1, Ting Mao1, Yongliang Zhang1, Mengle Shao1, Jia You1, Qiurong Ding1, Yan Chen1, Dongmei Wu1, Dong Xie1, Xu Lin1, Xiang Gao2, Randal J. Kaufman3, Wenjun Li1*, and Yong Liu1*
1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China.
2 Model Animal Research Center, Nanjing University, Nanjing 210093, China.
3 Departments of Biological Chemistry and Internal Medicine, Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48105, USA.
Autophosphorylation of inositol-requiring enzyme 1 (IRE1) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic β cells. We found that the scaffold protein receptor for activated C-kinase 1 (RACK1) interacted with IRE1 in a glucose-stimulated or endoplasmic reticulum (ER) stress–responsive manner in pancreatic β cells and primary islets. RACK1 mediated the glucose-inducible assembly of a complex containing IRE1, RACK1, and protein phosphatase 2A (PP2A) to promote dephosphorylation of IRE1 by PP2A, thereby inhibiting glucose-stimulated IRE1 activation and attenuating IRE1-dependent increases in insulin production. Moreover, IRE1 activation was increased and RACK1 abundance was decreased in a mouse model of diabetes. Thus, our findings demonstrate that RACK1 functions as a key component in regulating the IRE1 signaling pathway in pancreatic β cells.
