NEDD8 Ultimate Buster 1 Long (NUB1L) Protein Suppresses Atypical Neddylation and Promotes the Proteasomal Degradation of Misfolded Proteins

Li, Jie; Ma, Wenxia; Li, Huizhong; Hou, Ning; Wang, Xuejun; Kim, Il-man; Li, Faqian; Su, Huabo

doi:10.1074/jbc.m115.664375

Cited by 28 publications

(34 citation statements)

References 43 publications

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“…This patern likely represent atypical neddylation induced by Nedd8 overexpression, as described previously [16]. Consistent with previous studies, co-expression of NUB1 strongly decreased the abundance of these neddylated proteins [17]. However,this negative regulation of Nedd8 and of neddylated proteins was reversed by addition of the proteasome inhibitor MG132 (Fig 5A).…”

Section: Resultssupporting

confidence: 91%

Regulation of NUB1 Activity through Non-Proteolytic Mdm2-Mediated Ubiquitination

Bonacci¹,

Audebert²,

Camoin³

et al. 2017

PLoS ONE

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NUB1 (Nedd8 ultimate buster 1) is an adaptor protein which negatively regulates the ubiquitin-like protein Nedd8 as well as neddylated proteins levels through proteasomal degradation. However, molecular mechanisms underlying this function are not completely understood. Here, we report that the oncogenic E3 ubiquitin ligase Mdm2 is a new NUB1 interacting protein which induces its ubiquitination. Interestingly, we found that Mdm2-mediated ubiquitination of NUB1 is not a proteolytic signal. Instead of promoting the conjugation of polyubiquitin chains and the subsequent proteasomal degradation of NUB1, Mdm2 rather induces its di-ubiquitination on lysine 159. Importantly, mutation of lysine 159 into arginine inhibits NUB1 activity by impairing its negative regulation of Nedd8 and of neddylated proteins. We conclude that Mdm2 acts as a positive regulator of NUB1 function, by modulating NUB1 ubiquitination on lysine 159.

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Section: Resultssupporting

confidence: 91%

Regulation of NUB1 Activity through Non-Proteolytic Mdm2-Mediated Ubiquitination

Bonacci¹,

Audebert²,

Camoin³

et al. 2017

PLoS ONE

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“…45 Increased NEDD8 conjugates in end-stage failing human hearts were recently reported. 46 The present study identifies that CSN8/CSN and CRLs contribute to degradation of cytosolic misfolded proteins. This represents one major step closer to identification of specific Ub ligases for targeted degradation of toxic misfolded proteins; on the other hand, this also cautions that NAE inhibition may potentially exert cardiotoxicity, just like proteasome inhibitors.…”

Section: Discussionmentioning

confidence: 64%

COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity

Zhang

et al. 2015

Circulation Research

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Rationale Impaired degradation of misfolded proteins is associated with a large subset of heart diseases. Misfolded proteins are degraded primarily by the ubiquitin-proteasome system (UPS) but the ubiquitin ligases responsible for the degradation remain largely unidentified. The cullin deneddylation activity of the COP9 signalosome (CSN) requires all 8 CSN subunits (CSN1 through CSN8) and regulates cullin-RING ligases (CRLs), thereby controlling ubiquitination of a large number of proteins; however, neither CSN nor CRLs are known to regulate the degradation of cytosolic misfolded proteins. Objective We sought to investigate the role of CSN8/CSN in misfolded protein degradation and cardiac proteinopathy. Methods and Results Cardiac CSN8 knockout causes mouse premature death; hence, CSN8 haploinsufficiency (CSN8hypo) mice were used. Myocardial neddylated forms of cullins were markedly increased and myocardial capacity of degrading a surrogate misfolded protein was significantly reduced by CSN8hypo. When introduced into proteinopathic mice in which a bona fide misfolded protein CryABR120G is overexpressed in the heart, CSN8hypo aggravated CryABR120G-induced restrictive cardiomyopathy and shortened the lifespan of CryABR120G mice, which was associated with augmented accumulation of protein aggregates, increased neddylated proteins, and reduced levels of total ubiquitinated proteins and LC3-II in the heart. In cultured cardiomyocytes, both CSN8 knockdown and CRL inactivation suppressed the ubiquitination and degradation of CryABR120G but not native CryAB, resulting in accumulation of protein aggregates and exacerbation of CryABR120G cytotoxicity. Conclusions (1) CSN8/CSN promotes the ubiquitination and degradation of misfolded proteins and protects against cardiac proteotoxicity and (2) CRLs participate in degradation of cytosolic misfolded proteins.

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“…Proteins were extracted from ventricular myocardium tissues or cultured cells and subjected to SDS-PAGE as previously described [21]. Membranes were incubated overnight at 4°C with antibodies against GFP (sc-9996, 1:5000, Santa Cruz), ubiquitin (#04-263, 1:1000, Sigma-Aldrich), K48-ubiquitin (#8081, 1:1000, Cell Signaling Technology), GAPDH (SAB1405848, 1:6000, Sigma-Aldrich), β-tubulin (E7, 1:5000, Developmental Studies Hybridoma Bank) and PA28α (customized[22]).…”

Section: Methodsmentioning

confidence: 99%

“…Fluorescence confocal microscopy was performed as described previously[21]. Direct GFP fluorescence on O.C.T.-embedded ventricular myocardium sections (5 μm) was visualized using a Zeiss LSM 510 upright confocal microscope (Zeiss).…”

Section: Methodsmentioning

confidence: 99%

“…Isolation of total RNA and reverse transcription into single-stranded cDNA were performed as previously described[21]. Gene expression levels were measured in triplicate per biological sample by real-time PCR (StepOnePlus Real-Time PCR system, Life Technologies) using the SYBR-Green assay with gene-specific primers at a final concentration of 200 nM.…”

Section: Methodsmentioning

confidence: 99%

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Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy

Yue

et al. 2017

Journal of Molecular and Cellular Cardiology

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Background Diabetic cardiomyopathy is a major risk factor in diabetic patients but its pathogenesis remains poorly understood. The ubiquitin-proteasome system (UPS) facilitates protein quality control by degrading unnecessary and damaged proteins in eukaryotic cells, and dysfunction of UPS is implicated in various cardiac diseases. However, the overall functional status of the UPS and its pathophysiological role in diabetic cardiomyopathy have not been determined. Methods and results Type I diabetes was induced in wild-type and transgenic mice expressing a UPS functional reporter (GFPdgn) by injections of streptozotocin (STZ). STZ-induced diabetes progressively impaired cardiac UPS function as evidenced by the accumulation of GFPdgn proteins beginning two weeks after diabetes induction, and by a buildup of total and lysine (K) 48-linked polyubiquitinated proteins in the heart. To examine the functional role of the UPS in diabetic cardiomyopathy, cardiac overexpression of PA28α (PA28αOE) was used to enhance proteasome function in diabetic mouse hearts. PA28αOE diabetic mice displayed exhibited restoration of cardiac UPS function, as demonstrated by the diminished accumulation of GFPdgn and polyubiquitinated proteins. Moreover, PA28αOE diabetic mice exhibited reduced myocardial collagen deposition, decreased cardiomyocyte apoptosis, and improved cardiac systolic and diastolic function. Conclusion Impairment of cardiac UPS function is an early event in STZ-induced diabetes. Overexpression of PA28α attenuates diabetes-induced proteotoxic stress and cardiomyopathy, suggesting a potential therapeutic role for enhancement of cardiac proteasome function in this disorder.

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NEDD8 Ultimate Buster 1 Long (NUB1L) Protein Suppresses Atypical Neddylation and Promotes the Proteasomal Degradation of Misfolded Proteins

Cited by 28 publications

References 43 publications

Regulation of NUB1 Activity through Non-Proteolytic Mdm2-Mediated Ubiquitination

Regulation of NUB1 Activity through Non-Proteolytic Mdm2-Mediated Ubiquitination

COP9 Signalosome Controls the Degradation of Cytosolic Misfolded Proteins and Protects Against Cardiac Proteotoxicity

Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy

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