Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates

Zhong, Xiaoyan; Pittman, Randall N.

doi:10.1093/hmg/ddl164

Cited by 188 publications

(229 citation statements)

References 53 publications

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“…We provide mechanistic insight into this specific defect: Toxic polyQ-expanded proteins en-trap the ERAD proteins Ufd1, Npl4, and p97 (VCP) and thereby inhibit their essential participation in ERAD. Our results explain the molecular basis of the previously reported polyQ-induced unfolded protein response (UPR) and ER stress (Kouroku et al 2002;Nishitoh et al 2002;Thomas et al 2005) and, as noted in the Discussion, suggest that toxicity may be related to the normal function of SCA3 (Zhong and Pittman 2006). Further, we document that the dysfunction in ER protein homeostasis occurs with high specificity and is an early response, the first we detected after the expression of polyQ-expanded htt exonI.…”

supporting

confidence: 86%

Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity

Duennwald

Lindquist²

2008

Genes Dev.

272

296

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Protein misfolding, whether caused by aging, environmental factors, or genetic mutations, is a common basis for neurodegenerative diseases. The misfolding of proteins with abnormally long polyglutamine (polyQ) expansions causes several neurodegenerative disorders, such as Huntington's disease (HD). Although many cellular pathways have been documented to be impaired in HD, the primary triggers of polyQ toxicity remain elusive. We report that yeast cells and neuron-like PC12 cells expressing polyQ-expanded huntingtin (htt) fragments display a surprisingly specific, immediate, and drastic defect in endoplasmic reticulum (ER)-associated degradation (ERAD). We further decipher the mechanistic basis for this defect in ERAD: the entrapment of the essential ERAD proteins Npl4, Ufd1, and p97 by polyQ-expanded htt fragments. In both yeast and mammalian neuron-like cells, overexpression of Npl4 and Ufd1 ameliorates polyQ toxicity. Our results establish that impaired ER protein homeostasis is a broad and highly conserved contributor to polyQ toxicity in yeast, in PC12 cells, and, importantly, in striatal cells expressing full-length polyQ-expanded huntingtin. Polyglutamine (polyQ) expansions in proteins are the basis for at least nine different neurodegenerative disorders, including Huntington's disease (HD) (Orr and Zoghbi 2007). The proteins carrying polyQ expansions are broadly expressed, but each disease is characterized by the vulnerability of a particular subset of neurons. Interactions between sequences flanking the polyQ expansion and the proteome unique to distinct neurons must determine the specific character of each disease. However, in virtually every case, toxicity ensues when the expansion reaches ∼40 residues. Further, the age of disease onset decreases and the severity of disease progression increases as the length of the polyQ expansion increases. Thus, even though each disease is distinct, there must be common underlying toxic mechanisms related to polyQmediated misfolding.To investigate polyQ toxicity, we used a combination of yeast, PC12, and striatal cell models. We and others have developed yeast models that express N-terminal fragments of huntingtin (htt exonI) (Krobitsch and Lindquist 2000;Muchowski et al. 2000;Meriin et al. 2002; Duennwald et al. 2006a,b). Our yeast model recapitulates major features of neuronal polyQ pathology, including the hallmark feature of increasing toxicity with increasing polyQ length (Duennwald et al. 2006b). Thus, the yeast model presents the opportunity to identify factors that specifically determine polyQ toxicity in a genetically tractable model organism.Numerous cellular pathways, such as transcriptional regulation (Riley and Orr 2006), vesicular transport (Gunawardena and Goldstein 2005), and protein turnover (Bence et al. 2001;Bennett et al. 2007) are impaired by polyQ expansion proteins. It remains unclear, however, which of these cellular defects are initial and specific triggers of polyQ toxicity. Here, we focused on how the well-established polyQ-induced defect ...

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supporting

confidence: 86%

Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity

Duennwald

Lindquist²

2008

Genes Dev.

272

296

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“…involved in the degradation of mutant neuroserpin strongly suggests that VCP/p97 cooperates with Hrd1 and gp78 for neuroserpin degradation. The N-terminal fragments of polyQ-expanded huntingtin (Nhtt) and ataxin-3 inhibit the function of ERAD and retrotranslocation (33,34). In our observations, we also found that the polyQ-expanded Nhtt or ataxin-3 significantly stimulates mutant neuroserpin aggregation and perturbs its proteasomal degradation (data not shown).…”

Section: Discussionmentioning

confidence: 56%

“…In our observations, we also found that the polyQ-expanded Nhtt or ataxin-3 significantly stimulates mutant neuroserpin aggregation and perturbs its proteasomal degradation (data not shown). As the polyQexpanded Nhtt and ataxin-3 affect ERAD by influencing the VCP complex (33,34), and VCP deficiency significantly decreases mutant neuroserpin degradation rates (Fig. 2D), these data further suggest that the ERAD machinery is involved in mutant neuroserpin degradation.…”

Section: Discussionmentioning

confidence: 76%

The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin

Ying

Wang

Fan

et al. 2011

Journal of Biological Chemistry

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Familial encephalopathy with neuroserpin inclusion bodies is a neurodegenerative disorder characterized by the accumulation of neuroserpin polymers in the endoplasmic reticulum (ER) of cortical and subcortical neurons in the CNS because of neuroserpin point mutations. ER-associated degradation (ERAD) is involved in mutant neuroserpin degradation. In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. Overexpression of Hrd1 and gp78 decreases the mutant neuroserpin protein level, whereas Hrd1 and gp78 knockdown increases mutant neuroserpin stability. Moreover, ERAD impairment by mutant valosin-containing protein increases the mutant neuroserpin protein level and aggregate formation. Thus, these findings identify mutant neuroserpin as an ERAD target and show that Hrd1 and gp78 mediate mutant neuroserpin turnover through the ERAD pathway.Misfolding of specific proteins can lead to the formation of aggregates, which is associated with most neurodegenerative disorders. Protein aggregates are extracellular in Alzheimer's disease, cytosolic in Parkinson's disease and amyotrophic lateral sclerosis, both cytosolic and intranuclear in polyglutamine (polyQ) 3 diseases, and localize to the endoplasmic reticulum (ER) in familial encephalopathy with neuroserpin inclusion bodies (FENIB), which is caused by neuroserpin mutations (1). Although the role of the protein aggregates in the pathogenesis of these diseases is still poorly understood, a common feature of these aggregates is that they are all marked by ubiquitin. Neurodegenerative protein aggregation is closely related to the ubiquitin-proteasome system, a major cellular turnover system (2). Mutant neuroserpin aggregates have been observed in brain and cultured cells (3, 4). Neuroserpin is a secretory glycoprotein (5) that is a member of the serine protease inhibitor serpin family, and it is mainly expressed in the CNS (6). Mutations in neuroserpin result in its misfolding and accumulation in the ER (3, 4, 7). To date, four mutants of neuroserpin, S49P, S52R, H338R, and G392E, have been identified in association with FENIB (8). In FENIB-diseased brains, G392E, the most disruptive mutant, forms more inclusion bodies and at an earlier age of onset (13 years) than the other neuroserpin mutants (9). Because the earlier onset of FENIB is strongly correlated with the level of intracellular neuroserpin accumulation, neuroserpin accumulation appears to play a central role in FENIB pathology.Many accumulated proteins that are caused by mutations or ER stress are targeted by a protein quality control system, termed ER-associated degradation (ERAD). ERAD is a degradation system in which proteins that are misfolded in the ER are exported to the cytosol for proteasomal degradation (10, 11). ER-associated E3 ubiquitin ligases, together with the VCPUfd1-Npl4 complex, are key components of the ERAD machinery. During the ERAD process, selected proteins are ubiquitinated by E3 ubiquitin lig...

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“…For example, ataxin-3 interacts with ubiquitinproteasome pathway components (32)(33)(34), localizes to protein inclusions in various disease states (35,36), regulates the formation of aggresomes (37), and assists in degrading substrates retrotranslocated from the endoplasmic reticulum (34,38). In Drosophila, wild type ataxin-3 can suppress polyQ-mediated neurodegeneration through its ubiquitinbinding and cleavage activities, and expanded ataxin-3 retains this suppressor activity despite its pathogenic mutation (39).…”

mentioning

confidence: 99%

The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains

Winborn

Travis

Todi

et al. 2008

Journal of Biological Chemistry

236

320

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Ubiquitin chain complexity in cells is likely regulated by a diverse set of deubiquitinating enzymes (DUBs) with distinct ubiquitin chain preferences. Here we show that the polyglutamine disease protein, ataxin-3, binds and cleaves ubiquitin chains in a manner suggesting that it functions as a mixed linkage, chain-editing enzyme. Ataxin-3 cleaves ubiquitin chains through its amino-terminal Josephin domain and binds ubiquitin chains through a carboxyl-terminal cluster of ubiquitin interaction motifs neighboring the pathogenic polyglutamine tract.

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Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates

Cited by 188 publications

References 53 publications

Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity

Impaired ERAD and ER stress are early and specific events in polyglutamine toxicity

The Endoplasmic Reticulum (ER)-associated Degradation System Regulates Aggregation and Degradation of Mutant Neuroserpin

The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains

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