NEDD8 Ultimate Buster-1 Long (NUB1L) Protein Promotes Transfer of NEDD8 to Proteasome for Degradation through the P97UFD1/NPL4 Complex

Liu, Shuai; Ye, Hui; Zhao, Jian; Zhang, Yuhang; Song, Ai-Xin; Hu, Hongyu

doi:10.1074/jbc.m113.484816

Cited by 23 publications

(23 citation statements)

References 76 publications

(84 reference statements)

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“…These data demonstrate that NUB1L potently suppresses atypical neddylation but not typical neddylation. Supporting a role of NUB1L in NEDD8 degradation (20), NUB1L expression decreased free NEDD8 proteins (Fig. 3B).…”

Section: Journal Of Biological Chemistrymentioning

confidence: 55%

“…NUB1L Suppresses Atypical Neddylation-NUB1L overexpression has been shown to reduce neddylated proteins in non- cardiac cells (19,20), but it is not known whether endogenous NUB1L controls neddylation in cardiac and other cells. We created NUB1L wild-type and knockout MEFs.…”

Section: Proteotoxic Stress Induces Typical and Atypical Neddylation mentioning

confidence: 99%

“…It possesses a ubiquitin-like domain and three ubiquitin-associating domains. NUB1L specifically binds to NEDD8 and promotes the transfer of NEDD8 to the proteasome for degradation by cooperating with the p97UFD1-NPL4 complex (20). NUB1L overexpression has been shown previously to reduce neddylated proteins in non-cardiac cells (19).…”

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confidence: 99%

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

et al. 2015

Journal of Biological Chemistry

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Background: NEDD8 conjugates are increased in cells with proteasome function impairment, and neddylation of ubiquitinated proteins on the ubiquitin chain requires ubiquitin-but not NEDD8-activating enzyme. Results: NEDD8 ultimate buster 1 long (NUB1L) suppresses atypical neddylation and promotes the degradation of misfolded proteins. Conclusion: NUB1L is an important regulator of protein quality control. Significance: Selective targeting of atypical neddylation is a novel strategy to enhance protein quality control.

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Section: Journal Of Biological Chemistrymentioning

confidence: 55%

Section: Proteotoxic Stress Induces Typical and Atypical Neddylation mentioning

confidence: 99%

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

et al. 2015

Journal of Biological Chemistry

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“…The VCP-binding motif (VBM) was first identified in the DUB ataxin-3 (ATX3) and the ubiquitin ligase UBE4B [71] and has subsequently also been found in the ubiquitin ligase HRD1 [72], in the ubiquitin-dependent ER-resident rhomboid protease RHBDL4 [73], and in NUB1L, which is involved in the proteasomal degradation of NEDD8 [70,74]. The VBM is characterized by a core of four positively charged residues (Arg/Lys) with a highly conserved arginine at position four (consensus sequence EhRRRRL; h, hydrophobic amino acid) ( Fig.…”

Section: The Vcp-binding Motifmentioning

confidence: 99%

Control of p97 function by cofactor binding

2015

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Edited by Wilhelm JustKeywords: ATPases Associated with diverse cellular Activities p47 UFD1-NPL4 UBXD1 Inclusion Body Myopathy with Pagets disease of the bone and Fronto-temporal Dementia a b s t r a c t p97 (also known as Cdc48, Ter94, and VCP) is an essential, abundant and highly conserved ATPase driving the turnover of ubiquitylated proteins in eukaryotes. Even though p97 is involved in highly diverse cellular pathways and processes, it exhibits hardly any substrate specificity on its own. Instead, it relies on a large number of regulatory cofactors controlling substrate specificity and turnover. The complexity as well as temporal and spatial regulation of the interactions between p97 and its cofactors is only beginning to be understood at the molecular level. Here, we give an overview on the structural framework of p97 interactions with its cofactors, the emerging principles underlying the assembly of complexes with different cofactors, and the pathogenic effects of disease-associated p97 mutations on cofactor binding.

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“…As reported, P97 down-regulates the neddylation in cells, and knock-down of endogenous P97 increases the protein level of NEDD8 conjugates39. We performed co-transfection of HA-NEDD8 and the indicated forms of Atx3 respectively into HEK 293T cells, and detected the neddylation levels by Western blotting.…”

Section: Resultsmentioning

confidence: 84%

Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology

Liu

et al. 2014

Sci Rep

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115

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Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cellular proteins. We found that the aggregates formed by polyQ-expanded Atx3 sequester its interacting partners, such as P97/VCP and ubiquitin conjugates, into the protein inclusions through specific interactions both in vitro and in cells. Moreover, this specific sequestration impairs the normal cellular function of P97 in down-regulating neddylation. However, expansion of polyQ tract in Atx3 does not alter the conformation of its surrounding regions and the interaction affinities with the interacting partners, although it indeed facilitates misfolding and aggregation of the Atx3 protein. Thus, we propose a loss-of-function pathology for polyQ diseases that sequestration of the cellular essential proteins via specific interactions into inclusions by the polyQ aggregates causes dysfunction of the corresponding proteins, and consequently leads to neurodegeneration.

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NEDD8 Ultimate Buster-1 Long (NUB1L) Protein Promotes Transfer of NEDD8 to Proteasome for Degradation through the P97UFD1/NPL4 Complex

Cited by 23 publications

References 76 publications

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

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

Control of p97 function by cofactor binding

Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology

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