Proteolysis by the Ubiquitin-Proteasome System and Kidney Disease

Lecker, Stewart H.; Mitch, William E.

doi:10.1681/asn.2010090958

Cited by 28 publications

(25 citation statements)

References 32 publications

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“…Ubiquitin C (UBC) had the largest number of interactions (48) with the enzymes associated with our 13 metabolites; however, ubiquitin interactions with proteins are relatively nonspecific and it was not further evaluated. Nevertheless, the ubiquitin-proteasome system is known to be upregulated in the muscle of kidney disease patients and diabetic patients (23), and may indicate relevance of ubiquitin C in patients with diabetic kidney disease based on the urine metabolite profile. Indeed, among the top 5 bridge proteins, 3 proteins, MDM2, HUWE1, and CUL4B have been linked to ubiquitination.…”

Section: Resultsmentioning

confidence: 99%

Systems biology analysis reveals role of MDM2 in diabetic nephropathy

et al. 2016

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Section: Resultsmentioning

confidence: 99%

Systems biology analysis reveals role of MDM2 in diabetic nephropathy

et al. 2016

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“…38 The importance of the UPS in degrading proteins that impact cellular functions was recognized when the 2004 Nobel Prize in Chemistry was awarded to Hershko, Ciechanover and Rose. 23,39,40 …”

Section: Mechanisms Of Muscle Lossmentioning

confidence: 99%

Mechanisms of muscle wasting in chronic kidney disease

2014

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In patients with chronic kidney disease (CKD), loss of cellular proteins increases the risks of morbidity and mortality. Persistence of muscle protein catabolism in CKD results in striking losses of muscle proteins as whole-body protein turnover is great; even small but persistent imbalances between protein synthesis and degradation cause substantial protein loss. No reliable methods to prevent CKD-induced muscle wasting currently exist, but mechanisms that control cellular protein turnover have been identified, suggesting that therapeutic strategies will be developed to suppress or block protein loss. Catabolic pathways that cause protein wasting include activation of the ubiquitin–proteasome system (UPS), caspase-3, lysosomes and myostatin (a negative regulator of skeletal muscle growth). These pathways can be initiated by complications associated with CKD, such as metabolic acidosis, defective insulin signalling, inflammation, increased angiotensin II levels, abnormal appetite regulation and impaired microRNA responses. Inflammation stimulates cellular signalling pathways that activate myostatin, which accelerates UPS-mediated catabolism. Blocking this pathway can prevent loss of muscle proteins. Myostatin inhibition could yield new therapeutic directions for blocking muscle protein wasting in CKD or disorders associated with its complications.

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“…However, other proteolytic processes contribute to loss of muscle mass, including the uptake and degradation of certain extracellular or cell surface proteins or some cytosolic proteins by endocytosis into autophagic vacuoles that fuse with lysosomes (Lecker and Mitch, 2011; Mitch and Goldberg, 1996). In lysosomes, proteins are degraded by several acid-optimal proteases, including cathepsins B, H, L and D, and other acid hydrolases (Lecker et al, 2004).…”

Section: Ckd Stimulates Proteolytic Mechanisms In Musclementioning

confidence: 99%

“…Briefly, protein degradation in the UPS begins by concerted actions of enzymes that build a chain consisting of the heat shock protein cofactor, Ub onto substrate proteins, marking them for degradation (Lecker and Mitch, 2011; Reiter et al, 2009). The Ub chain leads to recognition of the protein by the 26S proteasome, a large multicatalytic protease complex that degrades Ub-conjugated proteins to small peptides (Lecker and Mitch, 2011). The initial Ub conjugation process requires ATP and three enzymatic components, the E1 (Ub-activating enzyme) and E2 (Ub-carrier or conjugating proteins) prepare Ub for its conjugation to the substrate protein.…”

Section: The Ubiquitin-proteasome System (Ups)mentioning

confidence: 99%

Muscle wasting from kidney failure—A model for catabolic conditions

Wang

2013

The International Journal of Biochemistry & Cell Biology

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Purpose Muscle atrophy is a frequent complication of chronic kidney disease (CKD) and is associated with increased morbidity and mortality. The processes causing loss of muscle mass are also present in several catabolic conditions. Understanding the pathogenesis of CKD-induced muscle loss could lead to therapeutic interventions that prevent muscle wasting in CKD and potentially, other catabolic conditions. Major findings Insulin or IGF-1 resistance caused by CKD, acidosis, inflammation, glucocorticoids or cancer causes defects in insulin-stimulated intracellular signaling that suppresses IRS-1 activity leading to decreased phosphorylation of Akt (p-Akt). A low p-Akt activates caspase-3 which provides muscle proteins substrates of the ubiquitin-proteasome system (UPS). A low p-Akt also leads to decreased phosphorylation of forkhead transcription factors which enter the nucleus to stimulate the expression of atrogin-1/MAFbx and MuRF1, E3 ubiquitin ligases that can be associated with proteolysis of muscle cells by the UPS. Caspase-3 also stimulates proteasome-dependent proteolysis in muscle. Summary in CKD, diabetes, inflammatory conditions or in response to acidosis or excess glucocorticoids, insulin resistance develops, initiating reduced IRS-1/PI3K/Akt signaling. In CKD, this reduces p-Akt which stimulates muscle proteolysis by activating caspase-3 and the UPS. Second, caspase-3 cleaves actomyosin yielding substrates for the UPS and increased proteasome-mediated proteolysis. Third, p-Akt down-regulation suppresses myogenesis in CKD. Fourth, exercise in CKD stimulates insulin/IGF-1 signaling to reduce muscle atrophy. Lastly, there is evidence that microRNAs influence insulin signaling providing a potential opportunity to design therapeutic interventions.

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Proteolysis by the Ubiquitin-Proteasome System and Kidney Disease

Cited by 28 publications

References 32 publications

Systems biology analysis reveals role of MDM2 in diabetic nephropathy

Systems biology analysis reveals role of MDM2 in diabetic nephropathy

Mechanisms of muscle wasting in chronic kidney disease

Muscle wasting from kidney failure—A model for catabolic conditions

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