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Sci. Signal., 26 January 2010
Vol. 3, Issue 106, p. ra7
[DOI: 10.1126/scisignal.2000514]

RESEARCH ARTICLES

Editor's Summary

Stress Control
Obesity and metabolic diseases, such as diabetes, are associated with endoplasmic reticulum (ER) stress and the accumulation of unfolded proteins in the ER, which activates the unfolded protein response (UPR). One of the mediators of the UPR is inositol-requiring enzyme 1{alpha} (IRE1{alpha}), which is autophosphorylated and activated in response to ER stress. In pancreatic β cells, IRE1{alpha} promotes insulin biosynthesis in response to acute glucose stimulation but inhibits this process after chronic glucose stimulation. To determine the mechanisms that mediate these different responses of IRE1{alpha} to glucose stimulation, Qiu et al. searched for previously unidentified binding partners of IRE1{alpha}. They found that the scaffold protein RACK1 interacted with IRE1{alpha} after glucose stimulation. Protein phosphatase 2A (PP2A) remained associated with RACK1 after acute glucose stimulation but dissociated from RACK1 after chronic glucose stimulation or the induction of ER stress. The differential association of PP2A with RACK1 accounted for stimulus-specific alterations in the phosphorylation and activation state of IRE1{alpha}. Islets from db/db mice, which are obese and mildly diabetic, showed decreased RACK1 abundance, as well as increased IRE1{alpha} phosphorylation and insulin content, and overexpression of RACK1 in these islets partially reversed these increases. Thus, RACK1 differentially modulates the activation of IRE1{alpha} in response to the duration of glucose stimulation and to ER stress, and RACK1-mediated regulation of IRE1{alpha} may be altered by prolonged metabolic stress.

Citation: Y. Qiu, T. Mao, Y. Zhang, M. Shao, J. You, Q. Ding, Y. Chen, D. Wu, D. Xie, X. Lin, X. Gao, R. J. Kaufman, W. Li, Y. Liu, A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1{alpha} Activation in Pancreatic β Cells. Sci. Signal. 3, ra7 (2010).

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