ER Protein Quality Control and the Unfolded Protein Response in the Heart

Arrieta, Adrian; Blackwood, Erik A; Glembotski, Christopher C.

doi:10.1007/82_2017_54

Cited by 36 publications

(42 citation statements)

References 90 publications

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“…The unfolded protein response (UPR) pathway is a well described stress coping mechanism to regain proteostasis in the ER by activation of several signaling pathways associated with ER-associated protein degradation (ERAD), autophagy, apoptosis and inflammatory signaling ( 3 , 78 – 83 ) (Figure 3 ). Proteostasis is essential to all the components of the CRN, but it is especially important for the ER to maintain proteostasis because this organelle is the site of membrane protein and lipid synthesis (Box 2, Figure 2 ).…”

Section: Cellular Stress Coping Strategies In the Heartmentioning

confidence: 99%

Stress Coping Strategies in the Heart: An Integrated View

Michalak

Agellon

2018

Front. Cardiovasc. Med.

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The heart is made up of an ordered amalgam of cardiac cell types that work together to coordinate four major processes, namely energy production, electrical conductance, mechanical work, and tissue remodeling. Over the last decade, a large body of information has been amassed regarding how different cardiac cell types respond to cellular stress that affect the functionality of their elaborate intracellular membrane networks, the cellular reticular network. In the context of the heart, the manifestations of stress coping strategies likely differ depending on the coping strategy outcomes of the different cardiac cell types, and thus may underlie the development of distinct cardiac disorders. It is not clear whether all cardiac cell types have similar sensitivity to cellular stress, how specific coping response strategies modify their unique roles, and how their metabolic status is communicated to other cells within the heart. Here we discuss our understanding of the roles of specialized cardiac cells that together make the heart function as an organ with the ability to pump blood continuously and follow a regular rhythm.

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Section: Cellular Stress Coping Strategies In the Heartmentioning

confidence: 99%

Stress Coping Strategies in the Heart: An Integrated View

Michalak

Agellon

2018

Front. Cardiovasc. Med.

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“…The increase in protein folding demand associated with nascent protein synthesis occurring during cardiac hypertrophy puts a strain on the global cellular framework responsible for balancing proteostasis, which is necessary to allow for proper cardiac myocyte growth and is critical to maintaining cardiac function [10][11][12][13][14][15]. Proteostasis is maintained by cellular networks that balance protein synthesis with proper folding, trafficking, and degradation [15,70].…”

Section: Proteostasismentioning

confidence: 99%

“…This proteolysis liberates an N-terminal 50 kD fragment of ATF6 that is able to freely translocate to the nucleus via a nuclear localization sequence (Figure 2, Step 3) [98] where it recognizes and binds to promoter regions containing canonical ATF6 binding motifs, such as the ER stress element (ERSE) [95]. For the most part, ATF6 is known for regulating canonical gene targets as part of an adaptive panel destined for the ER and designed to regulate ER protein folding (Figure 2, Steps 4 and 5) comprised of ER-resident chaperones (e.g., GRP78), PDIs, and ERAD components (e.g., HRD1) [11,14,16,18]. However, recent studies have illuminated a remarkable ability of ATF6 to induce non-canonical gene targets that were not previously known to be genes related to the UPR nor reside in the ER, but instead are induced by ATF6 in a stimulus-specific manner and localize to specific regions of cardiac myocytes including the lysosome [50], peroxisome [28] and sarcolemma (Figure 2 ① In its inactive state, ATF6 is a 90kD ER transmembrane protein that is anchored in the membrane in oligomers via GRP78 and intermolecular disulfide bonding.…”

Section: Atf6 Activationmentioning

confidence: 99%

“…Cardiac hypertrophy requires an increase in protein synthesis in cardiac myocytes, much of which is responsible for the sarcomere growth necessary to maintain or improve global cardiac contractile function [10,11]. This net increase in protein is determined primarily by the rates of the synthesis, characterized by an overall increase in cardiac mass, as well as chamber volume.…”

Section: Introductionmentioning

confidence: 99%

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Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis

Blackwood

Bilal

Stauffer

et al. 2020

Cells

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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.

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“…to the accumulation of misfolded proteins and proteotoxicity or proteinopathy (Hightower, 1991;Douglas and Cyr, 2010), which in cardiac myocytes is associated with ischemic heart disease, as well as hypertrophic and dilated cardiomyopathies (McLendon and Robbins, 2015;Arrieta et al, 2018). At the least, the misfolding of proteins can impair their functions, but of potentially greater impact is that misfolded proteins can form toxic polypeptides, aggregates, and pre-amyloid oligomers inside and outside of cells that broadly affect cardiac myocyte function and viability, leading to heart failure (Wang and Robbins, 2006;McLendon and Robbins, 2011;Parry et al, 2015).…”

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confidence: 99%

ATF6 as a Nodal Regulator of Proteostasis in the Heart

et al. 2020

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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.

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ER Protein Quality Control and the Unfolded Protein Response in the Heart

Cited by 36 publications

References 90 publications

Stress Coping Strategies in the Heart: An Integrated View

Stress Coping Strategies in the Heart: An Integrated View

Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis

ATF6 as a Nodal Regulator of Proteostasis in the Heart

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