IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation

Endoplasmic reticulum (ER) stress is among several pathological features that underlie beta-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact beta-cell survival but the underlying mechanisms remain unclear. Here we report that beta-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis. IRS1KOs exhibited low nuclear accumulation of spliced XBP-1 due to its poor stability, in contrast to elevated accumulation in IRS2KO. The reduced nuclear accumulation in IRS1KO was due to protein instability of Xbp1 secondary to proteasomal degradation. IRS1KO also demonstrated an attenuation in their general translation status in response to ER stress revealed by polyribosomal profiling. Phosphorylation of eEF2 was dramatically increased in IRS1KO enabling the beta-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca2+) was detected in IRS1KO beta-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for beta-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca2+ storage in the ER.