Proteasome dysfunction in cardiomyopathies

Gilda, Jennifer E.; Gomes, Aldrin V.

doi:10.1113/jp273607

Cited by 55 publications

(63 citation statements)

References 167 publications

(163 reference statements)

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“…Indeed, UPS impairment in mutant MYBPC3-knockin mice was not observed until 1 year of age (10). Our data suggest that UPS dysfunction in HCM is not directly caused by truncated MYBPC3 proteins, but rather may be an indirect consequence of pathological cardiac remodeling, as has been observed for other forms of cardiomyopathy and heart failure (40)(41)(42).…”

Section: Discussionsupporting

confidence: 62%

HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C

Glazier¹,

Hafeez²,

Mellacheruvu³

et al. 2018

JCI Insight

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Cardiac myosin binding protein C (MYBPC3) is the most commonly mutated gene associated with hypertrophic cardiomyopathy (HCM). Haploinsufficiency of full-length MYBPC3 and disruption of proteostasis have both been proposed as central to HCM disease pathogenesis. Discriminating the relative contributions of these 2 mechanisms requires fundamental knowledge of how turnover of WT and mutant MYBPC3 proteins is regulated. We expressed several disease-causing mutations in MYBPC3 in primary neonatal rat ventricular cardiomyocytes. In contrast to WT MYBPC3, mutant proteins showed reduced expression and failed to localize to the sarcomere. In an unbiased coimmunoprecipitation/mass spectrometry screen, we identified HSP70-family chaperones as interactors of both WT and mutant MYBPC3. Heat shock cognate 70 kDa (HSC70) was the most abundant chaperone interactor. Knockdown of HSC70 significantly slowed degradation of both WT and mutant MYBPC3, while pharmacologic activation of HSC70 and HSP70 accelerated degradation. HSC70 was expressed in discrete striations in the sarcomere. Expression of mutant MYBPC3 did not affect HSC70 localization, nor did it induce a protein folding stress response or ubiquitin proteasome dysfunction. Together these data suggest that WT and mutant MYBPC3 proteins are clients for HSC70, and that the HSC70 chaperone system plays a major role in regulating MYBPC3 protein turnover.

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Section: Discussionsupporting

confidence: 62%

HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C

Glazier¹,

Hafeez²,

Mellacheruvu³

et al. 2018

JCI Insight

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“…Furthermore, the 26S proteasomes purified from these brains have a reduced ability to hydrolyze ubiquitinated proteins, peptides and ATP (48). Impairment of proteasome function has also been found in a mouse model of Charcot Marie Tooth 1B neuropathy, which is caused by a mutation in Myelin Protein Zero (J. VerPlank and L. Wrabetz, unpublished), and in a mouse model of desmin-related cardiomyopathy (55, 56) (see below). Thus, proteasome defects seem to represent a common mechanism in human diseases caused by accumulation of aggregation-prone proteins.…”

Section: Therapeutic Potential Of Stimulating the Proteasome Via Agenmentioning

confidence: 90%

“…The finding that PKG stimulates proteasome activity in the heart also has potential therapeutic applications because there is growing evidence that impairment of the UPS contributes to the pathogenesis of several inherited cardiomyopathies (56). For example, desmin-related cardiomyopathy is caused by mutations in desmin, a muscle-specific intermediate filament protein, or by mutations in αβ-crystallin (Cryαβ), an abundant molecular chaperone that helps maintain desmin in its properly folded state (57).…”

Section: Protein Kinase G (Pkg) Enhances Proteasome Activity and Protmentioning

confidence: 99%

Regulating protein breakdown through proteasome phosphorylation

VerPlank

Goldberg

2017

Biochemical Journal

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The ubiquitin proteasome system degrades the great majority of proteins in mammalian cells. Countless studies have described how ubiquitination promotes the selective degradation of different cell proteins. However, there is a small but growing literature that protein half-lives can also be regulated by post-translational modifications of the 26S proteasome. This article reviews the ability of several kinases to alter proteasome function through subunit phosphorylation. For example, PKA and DYRK2 stimulate the proteasome’s ability to degrade ubiquitinated proteins, peptides, and ATP, while one kinase, ASK1, inhibits proteasome function during apoptosis. Proteasome phosphorylation is likely to be important in regulating protein degradation because it occurs downstream of many hormones and neurotransmitters, in conditions that raise cAMP or cGMP levels, after calcium influx following synaptic depolarization, and during phases of the cell cycle. Beyond its physiological importance, pharmacological manipulation of proteasome phosphorylation has the potential to combat various diseases. Inhibitors of phosphodiesterases by activating PKA or PKG can stimulate proteasomal degradation of misfolded proteins that cause neurodegenerative or myocardial diseases and even reduce the associated pathology in mouse models. These observations are promising since in many proteotoxic diseases, aggregation-prone proteins impair proteasome function and disrupt protein homeostasis. Conversely, preventing subunit phosphorylation by DYRK2 slows cell cycle progression and tumor growth. However, further research is essential to determine how phosphorylation of different subunits by these (or other) kinases alter the properties of this complex molecular machine and thus influence protein degradation rates.

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“…This complex task balances protein synthesis, folding, and degradation, with the latter relying on multiple systems (autophagy, calpains, proteasomes 4,5 ). Specifically, contributions to cardiac proteostasis by the Ub-proteasome system have been extensively reviewed 6,7 . Cardiac roles for modifications by other UbLs (NEDD8, SUMO) have also been described 8,9 .…”

mentioning

confidence: 99%

Putting the Stress on UFM1 (Ubiquitin-Fold Modifier 1)

Sutherland

Barrio

2018

Circ: Heart Failure

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Defects in protein homeostasis (also known as proteostasis) are intrinsically linked to age-related decline of cardiac function and likely contribute to cardiomyopathies. Protein-folding chaperones and protein quality control systems work overtime in the high stress cardiac environment, responding to wear and tear. Tight regulation of the pathway components is often controlled by post-translational modifications (PTMs). In addition to compact PTMs such as phosphorylation, bulkier PTMs involve ubiquitin (Ub) and other small ubiquitin-like (UbL) proteins, which are covalently conjugated to target proteins. These modifications can modify stability, localization, and function of the target protein. Ufm1 (ubiquitin-fold modifier 1) is a less-studied UbL, but modification by Ufm1 (ufmylation 1) is emerging as an important mediator of the endoplasmic reticulum (ER) stress response, which is activated in cardiomyocytes during heart failure. Focusing on Ufl1 (Ufm1-ligase 1), one of the enzymes that mediate ufmylation, the report from Huabo Su and colleagues 2 provides strong evidence that Ufl1 has a cardioprotective role and points to the ufmylation pathway as a potential target for pharmacological intervention for some cardiomyopathies.

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Proteasome dysfunction in cardiomyopathies

Cited by 55 publications

References 167 publications

HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C

HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C

Regulating protein breakdown through proteasome phosphorylation

Putting the Stress on UFM1 (Ubiquitin-Fold Modifier 1)

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