Abstract
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 and proliferation, we knocked down Ier3ip1 gene expression in mouse MIN6 insulinoma cells. IER3IP1 suppression induced apoptotic cell death which was associated with an increase in Bim and a decrease in Bcl-xL. Knockdown of Bim reduced apoptotic cell death in MIN6 cells induced by IER3IP1 suppression. Overexpression of the anti-apoptotic molecule Bcl-xL prevents cell death induced by IER3IP1 suppression. Moreover, IER3IP1 also regulates activation of the unfolded protein response (UPR). IER3IP1 suppression impairs the Inositol Requiring 1 (IRE1) and PKR-like ER kinase (PERK) arms of UPR. The cell proliferation of MIN6 cells was also decreased in IER3IP1 deficient cells. These results suggest that IER3IP1 suppression induces an increase in cell death and a decrease in cell proliferation in MIN6 cells, which may be the mechanism that mutations in IER3IP1 lead to diabetes.
Highlights
Immediate early response 3 interacting protein 1 (IER3IP1) is a highly conserved protein in different species and expressed in pancreas, heart, skeletal muscle, fetal brain cortex, kidney, liver, brain, placenta, lung and peripheral blood leukocytes [1, 2]
The propidium iodide (PI) staining positive cells were decreased from 60 ± 2% in Immediate Early Response 3 Interacting Protein 1 (IER3IP1) knock down (KD) cells to 27 ± 1% in Z-VAD/IER3IP1 KD cells (P
The results showed that IER3IP1 KD significantly increased the number of terminal dUTP nick end labeling (TUNEL) positive cells
Summary
Immediate early response 3 interacting protein 1 (IER3IP1) is a highly conserved protein in different species and expressed in pancreas, heart, skeletal muscle, fetal brain cortex, kidney, liver, brain, placenta, lung and peripheral blood leukocytes [1, 2]. Human IER3IP1 gene is located on human chromosome 18q12 and has 3 exons encoding an 82-amino acid protein. IER3IP1 contains 2 transmembrane domains and a putative G-patch domain found in several RNA-associated proteins and in type D retroviral polyproteins. IER3IP1 is localized to the endoplasmic reticulum (ER) through its C-terminal transmembrane domain [1]. IER3IP1 may be involved in transporting the proteins between the ER and the Golgi apparatus. Two homozygous missense mutations in IER3IP1 were found in two unrelated consanguineous families [1]. These mutations cause a unique clinical syndrome in which affected individuals display severe infantile epileptic encephalopathy, microcephaly, simplified gyral patterns, and permanent neonatal diabetes mellitus
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