Mutations in the gene for Immediate Early Response 3 Interacting Protein 1 (IER3IP1) cause permanent neonatal diabetes mellitus in human. The mechanisms involved have not been determined and the role of IER3IP1 in β-cell survival has not been characterized. In order to determine if there is a molecular link between IER3IP1 deficiency and β-cell survival, we knocked down IER3IP1 gene expression in mouse MIN6 insulinoma cells. IER3IP1 suppression induced apoptotic cell death which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown of Bim reduced apoptotic β-cell death induced by IER3IP1 suppression. Overexpression of the anti-apoptotic molecule Bcl-xL prevents β-cell death induced by IER3IP1 suppression. Moreover, IER3IP1 also regulates activation of the unfolded protein response (UPR). IER3IP1 suppression impairs the IRE1α and PERK arms of UPR. These results suggest that IER3IP1 suppression induces β-cell death by upregulating Bim and decreasing UPR activation. The studies in vivo also show the beta cell specific knockout IER3IP1 mice develop diabetes related to beta cell death and insulin secretion defect.


J. Sun: None. K. Polonsky: None. D. Ren: None.

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