Cell Biology

ER Stress and Diabetes

Science's STKE  26 Jun 2001:
Vol. 2001, Issue 88, pp. tw6
DOI: 10.1126/stke.2001.88.tw6

PERK (protein kinase R-like kinase) is a transmembrane protein located in the endoplasmic reticulum (ER) that phosphorylates the eukaryotic translation initiation factor 2α (eIF2α). Phosphorylation eIF2α by PERK contributes to translational repression in response to ER stress. PERK is highly expressed in several tissues including pancreas. PERK-/- mice demonstrate decreased phosphorylated eIF2α in pancreas, lung, and thymus; and in pancreas, IREα (a protein involved in mediating the ER stress response) activation is elevated, suggesting that this tissue is exhibiting enhanced ER stress because of the lack of ability to regulate translation rates. Consistent with this ER stress response, the ER of the PERK-/- mice was morphologically abnormal with dilated membranes and electron-dense material in the lumen. The PERK-/- mice demonstrate elevated blood glucose and decreased insulin secretion. The PERK-/- mice responded to a glucose challenge with a much higher rate of insulin biosynthesis, suggesting that one role of PERK is to moderate the glucose-mediated increases in insulin production to protect the ER from overload. Without this brake on the system, the cells undergo ER stress and ultimately die. This interpretation is based on the fact that there is a loss of insulin-producing cells in the pancreas due to apoptosis in the PERK-/- mice.

H. P. Harding, H. Zeng, Y. Zhang, R. Jungries, P. Chung, H. Plesken, D. D. Sabatini, D. Ron, Diabetes mellitus and exocrine pancreas dysfunction in PERK-/- mice reveals a role for translation control in secretory cell survival. Mol. Cell 7, 1153-1163 (2001). [Online Journal]