Research ArticleMetabolism

A Crucial Role for RACK1 in the Regulation of Glucose-Stimulated IRE1α Activation in Pancreatic β Cells

Sci. Signal.  26 Jan 2010:
Vol. 3, Issue 106, pp. ra7
DOI: 10.1126/scisignal.2000514

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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 1α (IRE1α), which is autophosphorylated and activated in response to ER stress. In pancreatic β cells, IRE1α 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 IRE1α to glucose stimulation, Qiu et al. searched for previously unidentified binding partners of IRE1α. They found that the scaffold protein RACK1 interacted with IRE1α 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 IRE1α. Islets from db/db mice, which are obese and mildly diabetic, showed decreased RACK1 abundance, as well as increased IRE1α phosphorylation and insulin content, and overexpression of RACK1 in these islets partially reversed these increases. Thus, RACK1 differentially modulates the activation of IRE1α in response to the duration of glucose stimulation and to ER stress, and RACK1-mediated regulation of IRE1α may be altered by prolonged metabolic stress.

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