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.
Highlights
PROTEOSTASIS AND PROTEOTOXICITYThe integrity of the proteome in cardiac myocytes is critical for normal heart function
Less studied is the proteostasis network associated with the endoplasmic reticulum (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
This review focuses on the ATF6 arm of the ER unfolded protein response (UPR) and its effects on the proteostasis network in the myocardium
Summary
The integrity of the proteome in cardiac myocytes is critical for normal heart function. Since disease- and age-related protein misfolding and proteotoxicity has been found in many organs, numerous studies have focused on discovering components of the proteostasis network in hopes of identifying potential targets for therapies to minimize the untoward effects of proteotoxicity on organ function These studies have revealed that mechanisms responsible for the surveillance of the structural integrity of nascent and mature proteins, as well as the processes that determine the fate of terminally misfolded proteins, reside in many cellular locations (Labbadia and Morimoto, 2015). It is thought that proteinfolding process results in as much as 30% of proteins never reaching their active folded configurations; such proteins are degraded either during or soon after translation (Schubert et al, 2000) This suggests that the elements of the proteostasis network that maintain proteome integrity must be physically located near nodal points of protein synthesis. While it has been less studied than calcium handling, the ER in cardiac myocytes is important for the synthesis of many membrane and secreted proteins that are important for viability and contractile function, including hormones, growth factors and stem cell homing factors, as well as ion channels and many other proteins that are critical for excitation-contraction coupling (Glembotski, 2012b)
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