ATF6 as a Nodal Regulator of Proteostasis in the Heart

Abstract

Proteostasis encompasses a homeostatic cellular network in all cells that maintains the integrity of the proteome, which is critical for optimal cellular function. The components of the proteostasis network include protein synthesis, folding, trafficking, and degradation. Cardiac myocytes have a specialized endoplasmic reticulum (ER) called the sarcoplasmic reticulum that is well known for its role in contractile calcium handling. However, less studied is the proteostasis network associated with the ER, which is of particular importance in cardiac myocytes because it ensures the integrity of proteins that are critical for cardiac contraction, e.g., ion channels, as well as proteins necessary for maintaining myocyte viability and interaction with other cell types, e.g., secreted hormones and growth factors. A major aspect of the ER proteostasis network is the ER unfolded protein response (UPR), which is initiated when misfolded proteins in the ER activate a group of three ER transmembrane proteins, one of which is the transcription factor, ATF6. Prior to studies in the heart, ATF6 had been shown in model cell lines to be primarily adaptive, exerting protective effects by inducing genes that encode ER proteins that fortify protein-folding in this organelle, thus establishing the canonical role for ATF6. Subsequent studies in isolated cardiac myocytes and in the myocardium, in vivo, have expanded roles for ATF6 beyond the canonical functions to include the induction of genes that encode proteins outside of the ER that do not have known functions that are obviously related to ER protein-folding. The identification of such non-canonical roles for ATF6, as well as findings that the gene programs induced by ATF6 differ depending on the stimulus, have piqued interest in further research on ATF6 as an adaptive effector in cardiac myocytes, underscoring the therapeutic potential of activating ATF6 in the heart. Moreover, discoveries of small molecule activators of ATF6 that adaptively affect the heart, as well as other organs, in vivo, have expanded the potential for development of ATF6-based therapeutics. This review focuses on the ATF6 arm of the ER UPR and its effects on the proteostasis network in the myocardium.

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

“…er of the basic leucine zipper family of transcription factors, with two main nucleus [43] -I, ERSE-II), UPR elements (UPRE) and cAMP response elements (CRE) gene transcription, up-regulates the expression of ER-related protein degradation, and enhances the cell's ability to fold protein [44][45][46].…”

AA147 ameliorates post-cardiac arrest cerebral ischemia/reperfusion injury through the co-regulation of the ATF6 and Nrf2 signaling pathways

“…The activated ATF6 can upregulate canonical ER stress response genes that encode ER chaperones (e.g., GRP78) and ER-associated protein degradation (ERAD) components ( Martindale et al, 2006 ; Shen et al, 2021 ). In addition, ATF6 also plays non-canonical roles in response to ER stress, such as activating several antioxidant genes, including catalase, to scavenge overproduced ROS ( Jin et al, 2017 ; Glembotski et al, 2020 ). The catalase functions in peroxisomes instead of an ER-resident protein, neutralizing a part of ROS caused by ischemia/reperfusion.…”

ER stress and calcium-dependent arrhythmias

“…Targeting the correct, harmful UPR branch in the specific disease setting is critical while other arms are activated to suppress detrimental SR protein loading ( Toko et al, 2010 ; Liu et al, 2022 ; Wang et al, 2022 ). For example, activation of the ATF6α branch of UPR is considered an adaptive responder to SR/ER stress and offers protective effects in many cardiac disease settings ( Glembotski et al, 2020 ). Ex vivo hearts from transgenic mice with ATF6α activation were protected from damage induced by ischemia reperfusion ( Martindale et al, 2006 ).…”