TY - JOUR
T1 - Sledgehammer to scalpel
T2 - Broad challenges to the heart and other tissues yield specific cellular responses via transcriptional regulation of the ER-stress master regulator ATF6α
AU - Stauffer, Winston T.
AU - Arrieta, Adrian
AU - Blackwood, Erik A.
AU - Glembotski, Christopher C.
N1 - Funding Information:
Funding: This research was funded by the American Heart Association (17PRE33670796), the National Institutes of Health (1F31HL140850, R01HL135893, R01 HL141463 and R01 HL149931) (C.C.G.), the San Diego State University (SDSU) Heart Institute (W.T.S., A.A., E.A.B., and C.C.G.), the Inamori Foundation (E.A.B.), and the ARCS Foundation, Inc, San Diego Chapter (W.T.S. and E.A.B). Additionally, W.T.S., A.A., and E.A.B are Rees-Stealy Research Foundation Phillips Gausewitz, M.D., Scholars of the SDSU Heart Institute.
Funding Information:
This research was funded by the American Heart Association (17PRE33670796), the National Institutes of Health (1F31HL140850, R01HL135893, R01 HL141463 and R01 HL149931) (C.C.G.), the San Diego State University (SDSU) Heart Institute (W.T.S., A.A., E.A.B., and C.C.G.), the Inamori Foundation (E.A.B.), and the ARCS Foundation, Inc, San Diego Chapter (W.T.S. and E.A.B). Additionally, W.T.S., A.A., and E.A.B are Rees-Stealy Research Foundation Phillips Gausewitz, M.D., Scholars of the SDSU Heart Institute.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
KW - ATF6α
KW - ATF6β
KW - Basic leucine-zipper
KW - Cardiac
KW - ER stress
KW - Endoplasmic reticulum
KW - OASIS
KW - Proteostasis
KW - Transcriptional regulation
KW - UPR
UR - http://www.scopus.com/inward/record.url?scp=85079295827&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85079295827&partnerID=8YFLogxK
U2 - 10.3390/ijms21031134
DO - 10.3390/ijms21031134
M3 - Review article
C2 - 32046286
AN - SCOPUS:85079295827
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1422-0067
IS - 3
M1 - 1134
ER -