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Corresponding author at: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
The UPS maintains the protein quality in the cell through the selective degradation of misfolded proteins.
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Autophagy is a bulk degradation system for maintaining cellular homeostasis.
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The unfolded protein response plays a prominent role in eliminating endoplasmic reticulum stress-mediated unfolded proteins.
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SUMOylation and NEDDylation regulate the protein quality via post translational protein modifications.
Abstract
Heart failure is a refractory disease with a prevalence that has continuously increased around the world. Over the past decade, we have made remarkable progress in the treatment of heart failure, including drug therapies, device therapies, and regeneration therapies. However, as each of these heart failure therapies does not go much beyond symptomatic therapy, there is a compelling need to establish novel therapeutic strategies for heart failure in a fundamental way. As cardiomyocytes are terminally differentiated cells, protein quality control is critical for maintaining cellular homeostasis, optimal performance, and longevity. There are five evolutionarily conserved mechanisms for ensuring protein quality control in cells: the ubiquitin-proteasome system, autophagy, the unfolded protein response, SUMOylation, and NEDDylation. Recent research has clarified the molecular mechanism underlying how these processes degrade misfolded proteins and damaged organelles in cardiomyocytes. In addition, a growing body of evidence suggests that deviation from appropriate levels of protein quality control causes cellular dysfunction and death, which in turn leads to heart failure. We herein review recent advances in understanding the role of protein quality control systems in heart disease and discuss the therapeutic potential of modulating protein quality control systems in the human heart.
Heart failure (HF) is a refractory clinical syndrome that originates from various types of structural or functional heart diseases. As the prevalence of HF has been steadily increasing, resulting in a consequent increase in mortality, HF is becoming a major public health concern worldwide. While we have made remarkable progress in developing HF therapeutic strategies, there is a compelling need to establish novel therapies for HF in a fundamental way, as none of these HF therapies constitute much more than symptomatic therapy.
Cardiomyocytes (CMs) are post-mitotic cells that must survive for a long time [
]. Therefore, it is crucial to maintain a balanced protein quality in order to minimize cellular dysfunction and death in this population and thereby prevent HF [
]. Protein quality control (PQC) systems are thought to be potential therapeutic targets of HF that can alleviate the damage to CMs, regardless of the HF etiology.
As PQC is critical for maintaining cellular homeostasis and integrity, this process is strictly regulated by multiple mechanisms. Once protein homeostasis is impaired, misfolded proteins and protein aggregates accumulate in the cells, which result in proteotoxicity. Increasing evidence suggests that impairment of PQC causes various diseases, including cancer, diabetes, neurodegenerative diseases, and cardiovascular diseases. It is also known that metabolic derangement in the cells is closely associated with the pathogenesis of various heart diseases [
]. In addition to maintaining protein homeostasis, PQC systems also play critical roles in controlling intracellular metabolism in CMs. Therefore, PQC is essential for protecting the heart from serious disorders in response to various stressors.
Protein homeostasis consists of gene transcription, translation, post-translational modification, complex formation, and protein degradation. Although research into PQC systems is lagging compared to that concerning gene expression regulatory systems, our understanding of the mechanisms for maintaining the protein quality has markedly developed over the past two decades. Among these mechanisms, the ubiquitin proteasome system (UPS) and autophagy are the most important proteolytic mechanisms for eliminating damaged organelles and misfolded proteins. To remedy protein-folding stress derived from the endoplasmic reticulum (ER), the unfolded protein response (UPR) behaves as an adaptive response [
]. As each proteolytic process plays different roles in regulating PQC in CMs, impairment of any of these regulatory mechanisms can result in heart disease [
]. This mechanism is initiated by the ATP-dependent activation of ubiquitin by E1 (activating enzymes). Activated ubiquitin is then transferred to E2 (conjugating enzymes), and E3 ubiquitin ligases interact with both the E2 and target substrates, thereby catalyzing the ubiquitin modification at lysine residues on target proteins and in turn elongating the poly-ubiquitin chain thereon.
Thus far, 2 E1-activating enzymes and 41 E2-conjugating enzymes have been detected in the human genome [
]. In contrast, there are numerous E3 ubiquitin ligases in humans to ensure the precise selectivity of protein recognition and degradation. A protein marked with poly-ubiquitin chains is delivered to the 26S proteasome, a protein complex composed of a 19S regulatory cap particle and 20S catalytic core. The 19S cap recognizes poly-ubiquitinated proteins, thereby promoting unfolding after de-ubiquitination. These processed proteins are then transferred to the interior of the 20S core to be degraded into small peptides by proteasomal peptidases (Fig. 1a). The UPS-mediated turnover of key regulatory molecules is associated with inflammation, cell cycle regulation, and cell death.
Fig. 1Schematic model of the molecular signaling pathways in the regulation of the ubiquitin proteasome system (UPS). (a, b) Hypothetical model of MuRF1 and calcineurin interactions during pressure overload (PO) in the heart. Expression of calcineurin is increased but that of MuRF1 is decreased in response to PO, and MuRF1 negatively regulates pathological hypertrophy in part through proteasomal degradation of calcineurin. (c) Hypothetical model of MAFbx, NF-κB, and IκB-α interactions in response to PO in the heart. Expression of both MAFbx and NF-κB is increased in response to PO, and MAFbx regulates pathological hypertrophy in part through proteasomal degradation of IκB-α and stabilization of NF-κB.
Cardiac hypertrophy is an adaptive consequence in response to various stressors, including pressure overload (PO), volume overload, and oxidative stress. However, excessive cardiac hypertrophic growth is maladaptive, which results in cardiac dysfunction. Increasing evidence suggests that the UPS plays critical roles in suppressing pathological cardiac hypertrophy. In a murine model of cardiac hypertrophy, deterioration of the proteasome activities precedes cardiac dysfunction [
]. Other investigations have shown that the proteasome activity is markedly decreased due to impairment of ATPase activity and following docking failure of the 19S regulatory cap to the 20S proteolytic core in failing hearts [
]. Furthermore, it is known that missense mutation in the MYBPC3 protein (E334K) inherited in an autosomal-dominant manner causes destabilization of the protein, which results in dysregulation of the UPS and subsequent left ventricular dilation and dysfunction [
Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy.
]. A previous study showed that MuRF1 negatively regulates cardiac hypertrophy and that mutations in TRIM63 (A48V, I130M, Q247del), the gene encoding MuRF1, are present in patients with hypertrophic cardiomyopathy [
Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy.
]. We previously demonstrated that endogenous MuRF1 alleviates cardiac hypertrophy and dysfunction during PO by suppressing the calcineurin-NFAT pathway (Fig. 1b) [
However, there are some opposing viewpoints concerning the role of the UPS in cardiac hypertrophy. Preclinical studies using both chronic canine and acute rodent models showed that PO induced elevation of proteasome activity [
]. As MAFbx promotes protein degradation specifically in striated muscle cells, just like MuRF1, it has been postulated that MAFbx would suppress cardiac hypertrophy. However, we showed that the downregulation of MAFbx inhibits cardiac hypertrophy through UPS-mediated destabilization of IkB-α and the subsequent activation of NF-kB (Fig. 1c) [
]. Thus, MAFbx is a potential target for pathological hypertrophy and subsequent HF.
Recently, proteasome inhibitors have become key drugs for the treatment of hematologic malignancies, such as multiple myeloma and non-Hodgkin’s lymphoma. Among these agents, bortezomib is used predominantly as a first-line chemotherapeutic agent. In contrast, carfilzomib, a second-generation proteasome inhibitor, is used in relapsed or refractory cases. A serious adverse effect of proteasome inhibitors is cardiac toxicity, including arrhythmia, hypertension, ischemic heart disease, cardiomyopathy, and HF [
]. As the prevalence of cardiac toxicity caused by proteasome inhibitors is relatively high, exploring how to prevent such adverse effects is a major issue in the field of cardio-oncology at present.
Ischemia/reperfusion (I/R) injury after myocardial infarction (MI) causes pathological remodeling, which results in serious cardiac dysfunction. The UPS is critically involved in the process of myocardial remodeling after I/R. As sudden elevation of reactive oxygen species (ROS) induced by reperfusion causes a tremendous amount of protein misfolding and damage, the UPS must operate at full capacity. The UPS is also critically associated with NFκB, a master regulator of inflammation that plays detrimental roles in the modulation of I/R-induced cardiac injury. The NFκB activity is positively regulated by the UPS through degradation of the endogenous IKK inhibitor IkBα. Consistently, the administration of 20S proteasome inhibitor exerts cardioprotective effects by suppressing the NFκB activity in pigs [
However, modulation of the UPS activity specifically in CMs produces different results from the above. The cardiac-specific inhibition of the UPS by CM-specific overexpression of a peptidase-disabled mutant of the 20S complex β5 subunit resulted in the exacerbation of cardiac injury in response to I/R [
]. Thus, further investigations should explore why the UPS mediates both detrimental and protective mechanisms under various stress conditions in the heart.
Autophagy and heart disease
Autophagy is an evolutionarily conserved mechanism for maintaining cellular homeostasis by degrading long-lived proteins and dysfunctional organelles [
]. Nutrient deprivation or lack of growth factor supplementation triggers the initiation of autophagy by phosphorylation of ULK1, a homolog of Atg1 in mammals, which results in the inactivation and dissociation of mammalian target of rapamycin (mTOR). Activated ULK1 also phosphorylates and recruits a class III phosphoinositide 3-kinase (PI3K) complex to the site of the formation of an isolation membrane to promote the generation of PI3P and further accumulation of Atgs at the nucleation site (Fig. 2).
Fig. 2Schematic model of the molecular signaling pathways in the regulation of the autophagic machinery. In autophagy machinery, double-membrane vesicles called autophagosomes sequester cellular components and deliver them to lysosomes for degradation.
Concurrently with this process, two ubiquitin-like conjugation systems participate in vesicle expansion and elongation. Atg12 activated by Atg7 (E1-like enzyme) is transferred to Atg10 (E2-like enzyme) to interact with Atg5 and Atg16L. The end product of this process—the Atg12-Atg5-Atg16L complex—functions as an E3-like ligase. This is the first conjugation system. Regarding the second conjugation system, LC3, a homolog of Atg8 in mammals, is initially processed by a cysteine protease Atg4 to expose a C-terminal glycine residue on it. LC3 activated by Atg7 is then transferred to Atg3 (E2-like enzyme). Finally, the Atg12-Atg5-Atg16L complex attaches phosphatidylethanolamine to LC3. Autophagosome formation is then completed by engulfing portions of cytoplasm using double-membrane vesicles. The completed autophagosome is delivered via vacuole to the lysosome, thereby forming an autolysosome. Finally, lysosomal acid lipases perform catalysis to degrade macromolecules into lipids, amino acids, carbohydrates, and nucleotides (Fig. 2).
Tremendous progress in our understanding of the molecular mechanisms underlying autophagy has been made in the past two decades. Along with these advances, research has additionally clarified the effects of autophagy on the physiology and pathophysiology in humans. Vici syndrome is an autosomal recessive mutation of the EPG5 gene (18q12.3) that results in neurodevelopmental and multisystem disorders, including cardiomyopathy. The EPG5 gene encodes ectopic P-granules autophagy protein 5 (EPG5), a Rab7 effector that mediates the fusion of autophagosomes with late endosomes [
]. Danon’s disease is an X-linked recessive mutation of the LAMP2 gene (Xq24) that results in severe cardiomyopathy and variable degrees of muscle weakness and is frequently associated with an intellectual deficit. The LAMP2 gene encodes LAMP2, an essential component of the lysosomal membrane that plays a critical role in autophagosome-lysosome fusion [
Increasing evidence suggests that autophagy plays a protective role in the heart at baseline. Phenotypic analyses of cardiac-specific Atg5 knockout mice have shown that the lack of a pro-autophagic molecule results in impairment of the cardiac function with the increased accumulation of protein aggregates in the cytoplasm at baseline [
]. Deposition of protein aggregates is commonly observed in various heart diseases, such as MI, load-induced cardiac hypertrophy, and dilated cardiomyopathy, although autophagy can be seen in the heart both at baseline and under stressed conditions [
]. Anthracyclines, including doxorubicin (DOX) and epirubicin, are widely used to treat a variety of malignancies, including lymphoma, leukemia, breast cancer, and sarcomas. However, the use of anthracyclines is limited because of their dose-dependent and cumulative cardiotoxicity. DOX is widely reported to promote protein aggregation partially by suppressing autophagy [
] wherein the Mst1-mediated phosphorylation of Beclin 1, a homolog of Atg6 in mammals, at Thr108 markedly promotes the interaction between Bcl-2/XL and Beclin 1, thereby inducing the homodimer formation of Beclin 1. As homodimerized Beclin 1 cannot activate class III PI3 kinase, the autophagy machinery is suppressed in this condition [
]. Phosphorylated Beclin 1 also induces displacement of Bcl-2/Bcl-xL from Bax and increases the amount of active Bax, thereby enhancing the apoptotic machinery. Thus, the activation of Mst1 worsens cardiac dysfunction not only by promoting apoptosis but also by suppressing autophagy below the physiological level. Consistently, we found that an increased amount of phosphorylated Beclin 1 by Mst1 downregulated autophagy and induced the excessive accumulation of aggresomes in the hearts of patients with end-stage dilated cardiomyopathy.
These observations prompted investigators to hypothesize that enhancement of the autophagy activity might ameliorate a worsened cardiac function. A previous investigation explored this issue using αB-Crystallin (Arg120Gly) transgenic (CryABR120G) mice [
]. CryABR120G mice are a model of desmin-related cardiomyopathies caused by inherited or de novo mutations in desmin and accessory proteins, including small heat shock protein CryAB. Impairment of the interaction between these proteins results in protein aggregation and myofibrillar disarray, thereby leading to severe and progressive cardiac dysfunction. The authors of this study showed that enhancing autophagy by crossing with cardiac-specific Atg7 transgenic mice ameliorates the cardiac function of CryABR120G mice.
TAT-Beclin 1 is a synthetic peptide derived from an internal region of Beclin 1 conjugated with the twin-arginine translocation protein transport system [
]. This peptide strongly promotes autophagy by mobilizing endogenous Beclin 1 through interacting with Golgi-associated plant pathogenesis-related protein 1, a negative regulator of autophagy. A previous investigation demonstrated that TAT-Beclin 1 administration improves PO-induced HF by promoting mitochondrial selective autophagy [
]. Thus, autophagy plays critical roles in maintaining a normal cardiac function via appropriate PQC.
In contrast, the excessive activation of autophagy may provoke myocardial death and cardiac dysfunction. In the case of I/R, suppression of autophagy attenuates myocardial injury during I/R in the mouse heart [
]. Furthermore, a previous investigation reported that excessive activation of autophagy beyond physiological levels induces autosis, a unique form of cell death [
]. These results suggest that the upregulation of autophagy in response to cardiac stressors may be detrimental. However, there are conflicting results regarding the effect of the upregulation of autophagy activity in response to I/R and PO [
]. Thus, the debate about whether or not activation of autophagy is beneficial under these pathological conditions is ongoing. To clarify this point, further analyses need be conducted. Collectively, these findings suggest that autophagy has a significant influence on the PQC in CMs for preserving the normal function of the heart.
The UPR and heart disease
Approximately 30% of proteins in cytosol are processed by ER. These proteins are translated, assembled, and folded in ER, and thus they are secreted from ER. In addition, these sequential processes are performed in a harmonized manner. Therefore, impairment of ER homeostasis by cellular stressors leads to the accumulation of unfolded proteins, which threatens the cell survival [
], thereby attenuating the translation of global protein synthesis, inducing the expression of UPR genes, and degrading excess protein through ER-associated degradation (ERAD) and autophagy machinery. However, if these adaptive mechanisms collectively fail to work properly due to excessive and persistent stress, apoptosis begins to act to protect host cells [
There are three major transducers of the UPR that convey the ER jeopardy to the nucleus. PKR-like ER kinase (PERK), a transmembrane protein kinase of the ER, is sequestered as an inactive form by interacting with GRP78 in the basal state. The increase in demand for protein folding liberates PERK from GRP78P, thereby activating it through autophosphorylation [
]. As the injured ER which suffers from stress needs ample time to recover, all translational activity should be downregulated. To this end, activated PERK then inhibits the translation initiation factor 2 α (eIF2α) activity by phosphorylation of the α subunit of eIF2α, thereby suppressing the formation of translation initiation complexes. However, phosphorylated eIF2α can also promote the translation of activating transcription factor 4 (ATF4) in a limited way. ATF4 promotes the expression of ER chaperones to facilitate protein folding. Similar to PERK, inositol-requiring 1 (IRE1) is inactivated by interacting with GRP78 in the basal state. ER stress promotes IRE1 dissociation from GRP78, thereby activating it through autophosphorylation, which in turn induces endoribonuclease activity. X-box binding protein 1 (XBP-1) is a major target of IRE1. Spliced XBP-1 (XBP-1s) modulated by IRE1 is a potent transcriptional activator that promotes gene expression coding for multiple chaperones and elements of ERAD. ATF6, the third element of the UPR, translocates from the ER to the Golgi apparatus when the binding partner of ATF6 is transferred to other interacting protein. After translocating to the Golgi apparatus, the cytoplasmic fragment of the cleaved ATF6 is translocated to the nucleus. This form of ATF6 then promotes the transcription of genes that encode ER chaperones [
]. A growing body of evidence suggests that perturbation of the UPR is critically involved in the pathogenesis of various disorders, including cancer and cardiovascular diseases (Fig. 3) [
Fig. 3Schematic model of the molecular signaling pathways in the regulation of the endoplasmic reticulum (ER) stress and the unfolded protein response (UPR).
As substantial biosynthesis of proteins and lipids is required in the process of cardiac hypertrophy, the protein folding load is very high in the ER of hypertrophied hearts. A previous report showed that transverse aortic constriction (TAC) strongly induces the markers of the UPR, and C/EBP homologous protein (CHOP), a downstream target of the UPR, is responsible for the detrimental effects of the UPR in response to PO in mice [
Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis.
A large number of studies has shown that the UPR is strongly induced in response to ischemia in the heart. A previous study demonstrated that the level of PDI, a UPR marker, is markedly elevated in the peri-infarct area of human myocardium [
]. The cardioprotective effects of the UPR are mediated through the induction of ER chaperones, which results in the enhancement of protein folding. Indeed, the increased expression of PDI plays a protective role in CMs both in vitro and in vivo [
]. Previous studies using mouse models have shown that I/R strongly induces the markers of UPR, including XBP-1s, GRP78, and eIF2α phosphorylation, in a time-dependent manner [
]. The upregulated UPR during I/R plays a protective role in the heart. Brief exposure to tunicamycin or thapsigargin to provoke therapeutic amounts of ER stress was able to ameliorate subsequent lethal I/R injury in rats [
Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6.
]. A recent study demonstrated that the administration of DOX downregulated the expression of XBP-1, although DOX enhanced the ATF6 activation in the hearts of mice [
]. The downregulation of XBP-1 resulted in the suppression of the GRP78 expression. In addition, DOX activated caspase-12, which induces CM apoptosis. The adeno-associated virus 9-mediated cardiac-specific overexpression of GRP78 or the administration of 4-phenylbutyrate, a chemical ER chaperone, attenuated caspase-12 cleavage and alleviated cardiac dysfunction induced by DOX in mice. Thus, therapeutic interventions targeting molecules of the UPR component and thereby reducing ER stress are promising potential strategies for treating HF [
]. This novel type of PQC, termed ER-phagy, can eliminate unfolded proteins, thereby effectively contributing to the maintenance of cellular homeostasis [
]. However, the role of ER-phagy in the heart remains to be elucidated.
SUMOylation, NEDDylation, and heart disease
Small ubiquitin-related modifier (SUMO) proteins, members of the ubiquitin-like protein family, play a critical role in PQC in CMs by promoting SUMOylation-mediated protein degradation. SUMOylation is a process wherein SUMO proteins are covalently attached to specific lysine residues in target proteins, thereby regulating various protein functions [
]. Similar to the UPS pathway, SUMOylation occurs through enzymatic cascades (Fig. 4). Initially, the C-terminal tails of the SUMO precursors are cleaved by sentrin-specific proteases (SENPs) to convert them to glycine (Gly)-Gly motif-exposed SUMO, an active form of SUMO protein. The Gly-Gly motif of the SUMO protein is then covalently conjugated with catalytic cysteine residues in the SUMO-activating enzyme E1 (SAE1/SAE2) to form a heterodimer via thioester bonding in an ATP-dependent manner. Ubiquitin-conjugating enzyme 9 (UBC9), a SUMO-conjugating E2 enzyme, then directly attaches the SUMO protein to a lysine in the substrates located within the consensus sequence of Ψ-K-X-E/D (Ψ: hydrophobic amino acid, X: any amino acid). After that, SUMO E3 ligases promote poly-SUMO chain formation. Finally, SUMOylated proteins are attached to the poly-ubiquitin chain by SUMO-targeted ubiquitin ligases, thereby linking SUMO modification to the UPS. Through this process, poly-SUMO chain-formed SUMO proteins are eliminated from substrates by SUMO-specific proteases, such as SENPs. The main difference between SUMOylation and the UPS is that SUMOylation itself does not degrade its target proteins in a direct manner (Fig. 4). Therefore, SUMOylation has diverse functions in the heart in addition to its direct effects toward PQC.
Fig. 4Schematic model of the molecular signaling pathways in the regulation of the SUMOylation and NEDDylation.
A previous study showed that the UBC9 expression is upregulated in response to the accumulation of misfolded proteins in CMs and myocardium derived from CryABR120G mice and TAC-operated mice. That study also revealed through gain- and loss-of-function experiments that UBC9 was able to strongly remove preamyloid oligomer (PAO) accumulated in myocardium, thus promoting UPS-mediated degradation and thereby alleviating cardiac dysfunction.
A number of congenital and acquired heart diseases are associated with dysregulation of SUMOylation. For example, the naturally occurring mutation of lamin A, a nuclear structural protein that plays a critical role in the maintenance and function of the nucleus, causes human familial dilated cardiomyopathy and abnormalities in the cardiac conduction system. As lamin A is a SUMO-2-favored substrate, the mutation of its target residues, including K201R, E203G, and E203K, resulted in altered subcellular localization and decreased SUMOylation activity, which consequently induced the impairment of the cardiac function [
NEDD8, a member of the ubiquitin-like protein family, plays a critical role in PQC in CMs via the NEDDylation-mediated regulation of both the UPS and autophagic pathway (Fig. 4) [
]. As with SUMOylation, NEDDylation modulates various biological processes, including nuclear transport, transcription DNA repair, cell cycle, and intracellular signaling. Initially, NEDD8 interacts with the heterodimeric UBA3, a NEDD-activating enzyme E1, in an ATP-dependent reaction. Ubiquitin-conjugating enzyme 12 (UBC12), the NEDD-conjugating E2 enzyme, is then directly conjugated with NEDD8, which attaches to cullin to form a complex with cullin-based RING ligases (CRLs), a group of E3 ubiquitin ligases. The COP9 signalosome (CSN)-mediated deNEDDylation of cullin is crucial for the proper functioning of CRLs. CSN is a multiprotein complex consisting of eight unique subunits (CSN1 through CSN8). The deletion of the CSN8 gene worsens both the UPS and autophagy machinery, resulting in the induction of severe dilated cardiomyopathy. This suggests that CSN8 plays a critical role in the cardiac PQC system [
]. Thus, NEDDylation is commonly mediated by NEDD8-specific enzymes (typical neddylation) but occasionally mediated by ubiquitin enzymes (atypical neddylation). The NEDD8 Ultimate Buster 1 Long (NUB1L) protein suppresses this proteolytic process and promotes proteasome-mediated degradation of misfolded proteins in the heart [
]. A recent investigation demonstrated that NEDDylation critically mediates ventricular chamber maturation by promoting degradation of Mst1 and LATS2 via the upregulation of Cullin 7, a NEDD8 substrate that acts as the ubiquitin ligase of Mst1 [
The UPS, autophagy, the UPR, SUMOylation, and NEDDylation are the major mechanisms responsible for the degradation of misfolded proteins in order to maintain an optimal cellular environment. Since these processes are critical mechanisms in the control of the protein quality in cells, their dysregulation or malfunction can cause heart disease, which ultimately results in HF. Despite dramatic developments in our understanding of the molecular mechanisms and roles of these proteolytic systems in the heart over the past two decades, most of these mechanisms have not yet been used in medical therapy for heart disease. Indeed, many unsolved questions remain regarding the association between the pathogenesis of HF and the PQC systems in the heart. Therefore, more studies exploring molecular targets of these proteolytic systems will be needed in order to establish effective treatments of HF through the modulation of PQC.
Funding
This work was supported in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (17K09570), Smoking Research Foundation, and Mochida Memorial Foundation for Medical and Pharmaceutical Research.
Disclosures
None.
Acknowledgments
I would like to thank express my special appreciation and thanks to my advisors Drs Junichi Sadoshima (Rutgers New Jersey Medical School, NJ, USA) and Mitsuaki Isobe (Sakakibara Heart Institute, Tokyo Japan), you have been tremendous mentors for me. I would like to thank you for encouraging my research.
Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy.
Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy.
Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis.
Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6.
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