From stress specificity to basal necessity: ATF6 uprising. Focus on 'pancreatic alpha-cells depend on basal expression of active ATF6alpha-p50 for cell survival even under nonstress conditions'

摘要

the unfolded protein response (UPR) is an adaptive mechanism aimed at restoring the homeostasis of the endoplasmic reticulum (ER) when it is perturbed (5). Three major ER stress transducers have been identified to date and include the proteins PKR-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6alpha) (6).ATF6alpha is a membrane-bound transcription factor that resides in the ER under basal conditions and is exported to the Golgi complex upon ER stress (2). In the Golgi apparatus, ATF6alpha is cleaved by the Site-1 and Site-2 proteases [SIP and S2P; (4)]. This subsequently leads to the release of the ATF6alpha cytosolic domain, which then acts as a transcription factor in the nucleus (11). In the ER, ATF6alpha activation depends on 7) the dissociation from the ER chaperone BiP/GRP78, which is titered away through accumulation of improperly folded proteins in the ER (7); and 2) the reduction of disulfide bridges within the ATF6alpha luminal domain (3).