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.
Highlights
In eukaryotes, transcription is a highly complex and regulated process involving multiple levels of control
The three sensor branches become active; (B) PERK, which has cytoplasmic kinase domains, dimerizes with itself and becomes autophosphorylated. It phosphorylates its substrate, eIF2α, in the cytoplasm which acts to slow translation of all non-unfolded protein response (UPR)-related proteins; (C) initiated by requiring protein-1 (IRE1), which has cytoplasmic kinase and endonuclease domains, dimerizes and is autophosphorylated. This activates its endonuclease function to splice out a section of XBP-1 mRNA to create a new, spliced transcript, XBP-1s, which codes for a transcription factor that upregulates some UPR-related transcripts; (D) activating transcription factor 6α (ATF6α), which is both a sensor of endoplasmic reticulum (ER) stress and a UPR-effector transcription factor, becomes monomeric upon induction of ER stress, whereupon it exits the ER via COPII vesicles and transits to the Golgi, where the active transcription factor is liberated from the transmembrane domain by Golgi proteases
PF429242 [34], inhibit ATF6α, but do so by inactivating serine proteases, including site 1 protease (S1P); a caveat to these compounds is that they impact other proteins that are activated by regulated intramembrane proteolysis (RIP), such as the transcription factor, sterol regulatory element binding protein (SREBP), as well as some other members of the ATF6 subgroup, including ATF6β [31,32]
Summary
Transcription is a highly complex and regulated process involving multiple levels of control. The processes that determine what genes are regulated by a given transcription factor are both intricate and varied At the least, these complex regulatory processes provide a mechanism for the fine-tuning of transcriptional programs involved in numerous responses including development, differentiation, immune responses and responses to stress. Example, as zinc finger, homeodomain, nuclear hormone basic helix-loop-helix andFor basic leucine certain stress-regulated transcription factors are responsive to oxygen depletion (e.g., hypoxiazipper (bZIP) [5]. Proteotoxic stress [10], i.e., protein-misfolding in the ER, but more recently has been found to be review focuses on activating transcription factor 6α (ATF6α), a transcription factor that was originally activated wider array ofproteotoxic stresses [11]. Found to by be aactivated by ER stress [10], i.e., protein-misfolding in the ER, but more recently has been found to be activated by a wider array of stresses [11]
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