Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis

Erik A. Blackwood, Khalid Azizi, Donna J. Thuerauf, Ryan J. Paxman, Lars Plate, Jeffery W. Kelly, R. Luke Wiseman and Christopher C. Glembotski ()
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Erik A. Blackwood: San Diego State University
Khalid Azizi: San Diego State University
Donna J. Thuerauf: San Diego State University
Ryan J. Paxman: The Scripps Research Institute
Lars Plate: The Scripps Research Institute
Jeffery W. Kelly: The Scripps Research Institute
R. Luke Wiseman: The Scripps Research Institute
Christopher C. Glembotski: San Diego State University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.

Date: 2019
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DOI: 10.1038/s41467-018-08129-2

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