Co-chaperone CHIP promotes aggregation of ataxin-1

Choi, Jung‐Hye; Ryu, Jeong Hee; Kim, Hyosun; Park, Sung Goo; Bae, Kwang‐Hee; Kang, Seung Kyu; Myung, Pyung Keun; Cho, Sayeon; Park, Byoung Chul; Lee, Do Hee

doi:10.1016/j.mcn.2006.10.002

Cited by 50 publications

(43 citation statements)

References 31 publications

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“…However, this co-chaperone is also involved in the unloading of the substrates from chaperone complex (Imai et al 2002). CHIP over-expression, while promoting poly-ubiquitylation, also leads to the accumulation of polyglutamine protein ataxin-1 in the insoluble fraction in cells (Choi et al 2007). The role(s) (G93A) were assessed by immunoblot analysis with anti-FLAG antibody.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the effects of Bag-1 on the half-lives of the client proteins differ greatly. For example, Bag-1 alone is sufficient to promote the degradation of polyglutamine protein ataxin-1 (Choi et al 2007), while it inhibits the degradation of Hsp70-associated Tau protein (Elliott et al 2007). When co-expressed with CHIP, Bag-1 further increases the CHIP-mediated degradation of GR (Demand et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Thus CHIP can provide a link between the chaperones and UPS and probably regulates the balance between protein refolding and degradation in the cells. Reportedly CHIP mediates the degradation of numbers of disease proteins linked to neurodegeneration Á e.g., a-synuclein (Shin et al 2005) and polyglutamine (polyQ) proteins (Jana et al 2005;Al-Ramahi et al 2006;Choi et al 2007). Notably CHIP promotes the degradation of mutant SOD1 without increasing its ubiquitylation (Choi et al 2004;Urushitani et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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CHIP promotes the degradation of mutant SOD1 by reducing its interaction with VCP and S6/S6′ subunits of 26S proteasome

Choi

Lee

2010

Animal Cells and Systems

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Previously we showed that CHIP, a co-chaperone of Hsp70 and E3 ubiquitin ligase, can promote the degradation of mutant SOD1 linked to familial amyotrophic lateral sclerosis (fALS) via a mechanism not involving SOD1 ubiquitylation. Here we present evidence that CHIP functions in the interaction of mutant SOD1 with 26S proteasomes. Bag-1, a coupling factor between molecular chaperones and the proteasomes, formed a complex with SOD1 in an hsp70-dependent manner but had no direct effect on the degradation of mutant SOD1. Instead, Bag-1 stimulated interaction between CHIP and the proteasome-associated protein VCP (p97), which do not associate normally. Over-expressed CHIP interferedwith the association between mutant SOD1 and VCP. Conversely, the binding of CHIP to mutant SOD1 was inhibited by VCP, implying that the chaperone complex and proteolytic machinery are competing for the common substrates. Finally we observed that mutant SOD1 strongly associated with the 19S complex of proteasomes and CHIP over-expression specifically reduced the interaction between S6/S6? ATPase subunits and mutant SOD1. These results suggest that CHIP, together with ubiquitin-binding proteins such as Bag-1 and VCP, promotes the degradation of mutant SOD1 by facilitating its translocation from ATPase subunits of 19S complex to the 20S core particle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CHIP promotes the degradation of mutant SOD1 by reducing its interaction with VCP and S6/S6′ subunits of 26S proteasome

Choi

Lee

2010

Animal Cells and Systems

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“…CHIP facilitates the ubiquitination and subsequent proteasomedependent degradation of several chaperone-bound client proteins such as p53 (Esser et al, 2005), ErbB2 (Zhou et al, 2003), cystic fibrosis transmembrane conductance regulator (Meacham et al, 2001), tau (Goryunov et al, 2007), Ask1 (Hwang et al, 2005), and ataxin-1 (Choi et al, 2007). Thus, these observations indicate that CHIP plays an important role in the regulation of cell growth, apoptosis, inflammation and neurodegeneration.…”

Section: Introductionmentioning

confidence: 89%

Genetic Screening for Mutations in the Chip Gene in Intracranial Aneurysm Patients of Chinese Han Nationality

Zhang²,

Zhang³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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We performed a case-control study to investigate whether SNPs of CHIP might affect the development of IA in Chinese Han nationality. We believe we are the first to have screened IA patients for mutations in the CHIP gene to determine the association with these variants. The study group comprised 224 Chinese Han nationality patients with at least one intracranial aneurysm and 238 unrelated healthy Han nationality controls. Genomic DNA was isolated from blood leukocytes. The entire coding regions of CHIP were genotyped by PCR amplification and DNA sequencing. Differences in genotype and allele frequencies between patients and controls were tested by the chi-square method. Genotype and allele frequencies of the SNP rs116166850 was demonstrated to be in Hardy-Weinberg equilibrium. No significant difference in genotype or allele frequencies between case and control groups was detected at the SNP. Our data do not support the hypothesis of a major role for the CHIP gene in IA development in the Chinese Han population.

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“…Overexpression of the chaperone-dependent aggregation in cellular models, suggesting that CHIP may exert different effects depending on its client protein [200]. Additionally, CHIP modulation was found to alter the levels of unexpanded ataxin-1 and -3 proteins in cells ( Table 7), indicating that CHIP can also regulate the degradation of wild-type forms of these proteins [33,200]. In agreement with the protective effects of CHIP overexpression, CHIP reduction increased mutant ataxin-3 aggregation and the severity of the phenotype in SCA3 transgenic mice [201].…”

Section: Genetic Modulation Of Molecular Chaperones In Scas and Drplamentioning

confidence: 99%

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

2016

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Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs, and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here we provide a focused review on Hsp90, Hsp70, and their cochaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer's and Parkinson's diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences.

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Co-chaperone CHIP promotes aggregation of ataxin-1

Cited by 50 publications

References 31 publications

CHIP promotes the degradation of mutant SOD1 by reducing its interaction with VCP and S6/S6′ subunits of 26S proteasome

CHIP promotes the degradation of mutant SOD1 by reducing its interaction with VCP and S6/S6′ subunits of 26S proteasome

Genetic Screening for Mutations in the Chip Gene in Intracranial Aneurysm Patients of Chinese Han Nationality

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

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