Pancreatic β-cells depend on basal expression of active ATF6α-p50 for cell survival even under nonstress conditions

Teodoro T, Odisho T, Sidorova E, Volchuk A. Pancreatic beta-cells depend on basal expression of active ATF6 alpha-p50 for cell survival even under nonstress conditions. Am J Physiol Cell Physiol 302: C992-C1003, 2012. First published December 21, 2011; doi:10.1152/ajpcell.00160.2011.-Activating transcription factor 6 (ATF6) is one of three principle endoplasmic reticulum (ER) stress response proteins and becomes activated when ER homeostasis is perturbed. ATF6 functions to increase ER capacity by stimulating transcription of ER-resident chaperone genes such as GRP78. Using an antibody that recognizes active ATF6 alpha-p50, we found that active ATF6 alpha was detected in insulinoma cells and rodent islets even under basal conditions and the levels were further increased by ER stress. To examine the function of ATF6 alpha-p50, we depleted endogenous ATF6 alpha-p50 levels using small interfering RNA in insulinoma cells. Knockdown of endogenous ATF6 alpha-p50 levels by similar to 60% resulted in a reduction in the steady-state levels of GRP78 mRNA and protein levels in nonstressed cells. Furthermore, ATF6 alpha knockdown resulted in an apoptotic phenotype. We hypothesized that removal of the ATF6 alpha branch of the unfolded protein response (UPR) would result in ER stress. However, neither the PKR-like endoplasmic reticulum kinase (PERK), nor the inositol requiring enzyme 1 (IRE1) pathways of the UPR were significantly activated in ATF6 alpha knockdown cells, although these cells were more sensitive to ER stress-inducing compounds. Interestingly, phosphorylation of JNK, p38, and c-Jun were elevated in ATF6 alpha knockdown cells and inhibition of JNK or p38 kinases prevented apoptosis. These results suggest that ATF6 alpha may have a role in maintaining beta-cell survival even in the absence of ER stress.