TY - JOUR
T1 - Designing Novel Therapies to Mend Broken Hearts
T2 - ATF6 and Cardiac Proteostasis
AU - Blackwood, Erik A.
AU - Bilal, Alina S.
AU - Stauffer, Winston T.
AU - Arrieta, Adrian
AU - Glembotski, Christopher C.
PY - 2020/3/3
Y1 - 2020/3/3
N2 - The heart exhibits incredible plasticity in response to both environmental and genetic alterations that affect workload. Over the course of development, or in response to physiological or pathological stimuli, the heart responds to fluctuations in workload by hypertrophic growth primarily by individual cardiac myocytes growing in size. Cardiac hypertrophy is associated with an increase in protein synthesis, which must coordinate with protein folding and degradation to allow for homeostatic growth without affecting the functional integrity of cardiac myocytes (i.e., proteostasis). This increase in the protein folding demand in the growing cardiac myocyte activates the transcription factor, ATF6 (activating transcription factor 6α, an inducer of genes that restore proteostasis. Previously, ATF6 has been shown to induce ER-targeted proteins functioning primarily to enhance ER protein folding and degradation. More recent studies, however, have illuminated adaptive roles for ATF6 functioning outside of the ER by inducing non-canonical targets in a stimulus-specific manner. This unique ability of ATF6 to act as an initial adaptive responder has bolstered an enthusiasm for identifying small molecule activators of ATF6 and similar proteostasis-based therapeutics.
AB - The heart exhibits incredible plasticity in response to both environmental and genetic alterations that affect workload. Over the course of development, or in response to physiological or pathological stimuli, the heart responds to fluctuations in workload by hypertrophic growth primarily by individual cardiac myocytes growing in size. Cardiac hypertrophy is associated with an increase in protein synthesis, which must coordinate with protein folding and degradation to allow for homeostatic growth without affecting the functional integrity of cardiac myocytes (i.e., proteostasis). This increase in the protein folding demand in the growing cardiac myocyte activates the transcription factor, ATF6 (activating transcription factor 6α, an inducer of genes that restore proteostasis. Previously, ATF6 has been shown to induce ER-targeted proteins functioning primarily to enhance ER protein folding and degradation. More recent studies, however, have illuminated adaptive roles for ATF6 functioning outside of the ER by inducing non-canonical targets in a stimulus-specific manner. This unique ability of ATF6 to act as an initial adaptive responder has bolstered an enthusiasm for identifying small molecule activators of ATF6 and similar proteostasis-based therapeutics.
KW - ATF6
KW - cardiac myocyte
KW - cardiomyopathy
KW - hypertrophy
KW - proteostasis
KW - small molecule
KW - therapy
KW - transcriptional regulation
KW - unfolded protein response (UPR)
UR - http://www.scopus.com/inward/record.url?scp=85102716248&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102716248&partnerID=8YFLogxK
U2 - 10.3390/cells9030602
DO - 10.3390/cells9030602
M3 - Review article
C2 - 32138230
AN - SCOPUS:85102716248
VL - 9
JO - Cells
JF - Cells
SN - 2073-4409
IS - 3
ER -