Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms

Abstract

Many forms of cardiac disease, including heart failure, present with inadequate protein quality control (PQC). Pathological conditions often involve impaired removal of terminally misfolded proteins. This results in the formation of large protein aggregates, which further reduce cellular viability and cardiac function. Cardiomyocytes have an intricately collaborative PQC system to minimize cellular proteotoxicity. Increased expression of chaperones or enhanced clearance of misfolded proteins either by the proteasome or lysosome has been demonstrated to attenuate disease pathogenesis, whereas reduced PQC exacerbates pathogenesis. Recent studies have revealed that phosphorylation of key proteins has a potent regulatory role, both promoting and hindering the PQC machinery. This review highlights the recent advances in phosphorylations regulating PQC, the impact in cardiac pathology, and the therapeutic opportunities presented by harnessing these modifications.

Keywords: autophagy; cardiac disease; chaperones; phosphorylation; proteasome; ubiquitin enzymes.

FIGURE 1

An overview of protein quality control systems. Misfolded proteins may regain native structure with the assistance of chaperones, however if proper re-folding cannot occur the misfolded protein will be catalyzed by the UPS through ubiquitination via a series of enzymatic reactions involving an ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) for degradation by the proteasome (A). Chaperone mediated autophagy (CMA) is a process by which the heat shock cognate 70 (HSC70) complex recognizes and binds select protein targets for internalization and degradation to the lysosome through the lysosome associated membrane protein 2A (LAMP2A) receptor (B). Macroautophagy is the bulk removal of proteins, protein aggregates, and organelles by first forming an autophagosome to surround the cargo followed by merger with the lysosome for degradation (C). Microautophagy is a process by which the lysosome invaginates to bring protein substrates into the lysosome for degradation (D).

FIGURE 2

An illustration of the development of cardiac proteinopathy. Cardiomyocytes accumulate ubiquitinated and aggregated proteins as a result of impaired PQC mechanisms. The failure of cardiomyocyte chaperones activity to efficiently re-fold misfolded proteins results in misfolded proteins aggregating, which impairs the proteasome and overwhelms autophagy. Insufficient PQC exacerbates disease pathogeneses (e.g., cardiac hypertrophy and atherosclerosis).

FIGURE 3

Positive and negative regulators of the ubiquitin proteasome system. Proteins that positively (green box) and negatively (red box) regulate cardiomyocyte chaperones, ubiquitination enzymes, and the proteasome.

FIGURE 4

A diagram of the regulators of autophagy. An overview of protein degradation via autophagy and its regulators, both positively (green box) and negatively (red box).