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

Tomozumi Takatani, Jun Shirakawa, Michael W. Roe, Colin A. Leech, Bernhard Maier, Raghu Mirmira, Rohit N. Kulkarni

Research output: Contribution to journalArticle

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Abstract

Endoplasmic reticulum (ER) stress is among several pathological features that underlie β-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 β-cell survival but the underlying mechanisms remain unclear. Here we report that β-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 β-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca2+) was detected in IRS1KO β-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for β-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca2+ storage in the ER.

Original languageEnglish (US)
Article number28177
JournalScientific Reports
Volume6
DOIs
StatePublished - Jul 5 2016

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Insulin Receptor Substrate Proteins
Endoplasmic Reticulum Stress
Protein Biosynthesis
Apoptosis
Endoplasmic Reticulum
Cytoprotection
Somatomedins
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Cell Survival
Proteins
Cell Death
Phosphorylation
Insulin
Calcium

ASJC Scopus subject areas

  • General

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IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation. / Takatani, Tomozumi; Shirakawa, Jun; Roe, Michael W.; Leech, Colin A.; Maier, Bernhard; Mirmira, Raghu; Kulkarni, Rohit N.

In: Scientific Reports, Vol. 6, 28177, 05.07.2016.

Research output: Contribution to journalArticle

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AU - Maier, Bernhard

AU - Mirmira, Raghu

AU - Kulkarni, Rohit N.

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