Sledgehammer to Scalpel: Broad Challenges to the Heart and Other Tissues Yield Specific Cellular Responses via Transcriptional Regulation of the ER-Stress Master Regulator ATF6?.

ABSTRACT: There are more than 2000 transcription factors in eukaryotes, many of which are subject to complex mechanisms fine-tuning their activity and their transcriptional programs to meet the vast array of conditions under which cells must adapt to thrive and survive. For example, conditions that impair protein folding in the endoplasmic reticulum (ER), sometimes called ER stress, elicit the relocation of the ER-transmembrane protein, activating transcription factor 6? (ATF6?), to the Golgi, where it is proteolytically cleaved. This generates a fragment of ATF6? that translocates to the nucleus, where it regulates numerous genes that restore ER protein-folding capacity but is degraded soon after. Thus, upon ER stress, ATF6? is converted from a stable, transmembrane protein, to a rapidly degraded, nuclear protein that is a potent transcription factor. This review focuses on the molecular mechanisms governing ATF6? location, activity, and stability, as well as the transcriptional programs ATF6? regulates, whether canonical genes that restore ER protein-folding or unexpected, non-canonical genes affecting cellular functions beyond the ER. Moreover, we will review fascinating roles for an ATF6? isoform, ATF6?, which has a similar mode of activation but, unlike ATF6?, is a long-lived, weak transcription factor that may moderate the genetic effects of ATF6?.

SUBMITTER: Stauffer WT 

PROVIDER: S-EPMC7037772 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature