A series of diverse mechanisms are brought to bear on defective protein degradation Chaperones are the first line of defense, participating in either the initial folding, or refolding of unfolded/misfolded proteins during or after protein synthesis Indeed, preventing the accumulation of misfolded proteins begins during translation as chaperones attach to many nascent, growing peptides such that an estimated 30% of translated proteins never reach their final cellular destination These newly synthesized nascent proteins are recognized as being misfolded or are unable to be folded correctly and are degraded almost immediately after or even during translation.130 Heat shock proteins are perhaps the most intensely studied chaperones, and their importance in cardiac function is well documented.131 However, chaperones are only a part of the multifaceted protein quality control machinery, which consists not only of constitutive and inducible chaperones but also engages compartment-specific mechanisms such as the unfolded protein response pathways in the endoplasmic reticulum or the heat shock response in the nuclear and cytoplasmic compartments The endoplasmic reticulum (ER) stress response, also referred to as the unfolded protein response, is another important protein quality control mechanism in the heart Three transmembrane ER proteins (PERK, IRE1 and ATF6) are activated by misfolded proteins in the ER, stimulating the translocation of transcription factors ATF4, ATF6, and XBP1 This then activates proteins that comprise the ER stress response, including chaperones, targeting the misfolded proteins for degradation by the proteasome (see below).132 Unsurprisingly, ER stress is induced with cardiac injury including ischemia, pathologic hypertrophy, and heart failure.132 However, the main system of defense for ridding the cardiomyocyte of damaged or misfolded protein is the ubiquitin proteasome system This system mediates the turnover of most cellular proteins by degrading terminally misfolded proteins via proteasomal proteolysis.133,134 The proteasome is a large, multisubunit complex tasked with the degradation of monomeric proteins and the majority of misfolded protein species are eliminated from the cell using this mechanism.135 For proteasomal degradation, the proteins must first be posttranslationally modified by the process of ubiquitination Ubiquitination involves three main steps: activation, conjugation, and ligation, which take place through the sequential actions of a series of reactions catalyzed by the E1, E2, and E3 enzymes, respectively The damaged protein is first covalently conjugated to a series of ubiquitin monomers at specific lysine residues through an isopeptide bond, serine or threonine residues via an ester linkage, or at the N- terminus through a peptide bond with the amino group of the methionine.136 Through multiple catalytic rounds, successive ubiquitins are linked to the attached (growing) chain at either one of seven lysines or the terminal methionine, growing into a poly-ubiquitin chain, although mono-ubiquitination sometimes occurs The modified protein is then recognized by transport proteins and trafficked to the proteasome for subsequent proteolysis The proteasome is equipped with proteases, which have cleavage activities similar to trypsin, chymotrypsin, and caspases that enable most proteins to be degraded within the proteasomal cavity or bore The fidelity of this process is critical; malfunction or decreased proteasomal proteolysis will lead to misfolded protein accumulation and cellular dysfunction.135,137 Interestingly, proteasomal activity is impaired in a number of heart failure models,138 and proteasomal activity is a therapeutic target in treatment of different blood cancers, with inhibitors of the 20S proteasome, such as bortezomib or marizomib, validated in clinical trials.139 There has been interest in enhancing proteasomal activity and subsequently ascertaining if cardiac function is maintained in the face of an acute or chronic proteotoxic insult In a series of experiments utilizing crosses between different transgenic mice, Wang and colleagues showed that enhancement of the proteolytic function of the proteasome was beneficial in cardiac protein conformation-based disease or in ischemia-reperfusion injury,140 although clearly in some contexts of cardiac disease, increased proteasomal flux can be detrimental.141 The proteasome's activity is dependent on the targeted protein being internalized into the catalytic bore of the cylinder formed by the proteasomal protein complex This imposes size limits, as the bore's internal diameter is, at most, 53 Angstroms.142 However, during proteotoxic stress, large proteinaceous aggregates or cell organelle damage occurs, resulting in cellular debris too large to be degraded by the proteasome When this occurs, the quality control mechanism autophagy comes into play Autophagy (“self-eating”) refers to a cell's ability to recycle proteins and damaged organelles It is a normal process that is essential during normal development and maturation, as well as for normal maintenance of cell function Autophagy can serve many purposes and its modulation, either up or down, may be beneficial or pathogenic, depending on the cellular context, underlying disease, and developmental stage However, in the face of a proteotoxic insult in the heart, autophagy can serve as the primary clearance mechanism for proteinaceous aggregates or even damaged mitochondria and other organelles too large for proteasomal degradation Macroautophagy involves the engulfment of the components destined for degradation into double-membrane vesicles known as autophagosomes, which fuse with lysosomes or endosomes to promote degradation Typical cargo degraded during autophagy includes misfolded proteins and defective organelles Because autophagosomes can accommodate much larger cargo than the proteasome, they serve as the primary degradation route for these large damaged cellular components.143,144 Compromised autophagy, in the context of proteotoxic heart disease, presents an increased pathogenic insult and can lead to increased morbidity and accelerated heart failure Decreased autophagic flux has been noted in many disease processes but autophagy is very context dependent and restoration of normal or even enhanced autophagy can be beneficial145 or pathogenic.146