Sledgehammer to scalpel: Broad challenges to the heart and other tissues yield specific cellular responses via transcriptional regulation of the ER-stress master regulator ATF6α

Winston T. Stauffer, Adrian Arrieta, Erik A. Blackwood, Christopher C. Glembotski

Research output: Contribution to journalReview articlepeer-review

4 Scopus citations

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 6α (ATF6α), to the Golgi, where it is proteolytically cleaved. This generates a fragment of ATF6α 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, ATF6α 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 ATF6α location, activity, and stability, as well as the transcriptional programs ATF6α 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 ATF6α isoform, ATF6β, which has a similar mode of activation but, unlike ATF6α, is a long-lived, weak transcription factor that may moderate the genetic effects of ATF6α.

Original languageEnglish (US)
Article number1134
JournalInternational journal of molecular sciences
Volume21
Issue number3
DOIs
StatePublished - Feb 1 2020
Externally publishedYes

Keywords

  • ATF6α
  • ATF6β
  • Basic leucine-zipper
  • Cardiac
  • ER stress
  • Endoplasmic reticulum
  • OASIS
  • Proteostasis
  • Transcriptional regulation
  • UPR

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint

Dive into the research topics of 'Sledgehammer to scalpel: Broad challenges to the heart and other tissues yield specific cellular responses via transcriptional regulation of the ER-stress master regulator ATF6α'. Together they form a unique fingerprint.

Cite this