Global Impairment of the Ubiquitin-Proteasome System by Nuclear or Cytoplasmic Protein Aggregates Precedes Inclusion Body Formation

Bennett, Eric J.; Bence, Neil; Rajadas, Jayakumar; Kopito, Ron R.

doi:10.1016/j.molcel.2004.12.021

Cited by 464 publications

(370 citation statements)

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“…Indeed, several studies have shown that sequestration of metastable and essential cellular factors such as proteins involved in chromatin remodeling, transcription, translation, nuclear import and cytoskeletal structure by the aggregates is the major cause of observed toxicity in vivo (Bucciantini et al, 2002;Chai et al, 2002;Olzscha et al, 2011;Suhr et al, 2001). Aggregates can also interfere with the cellular defense mechanisms by altering protein folding homeostasis (Gidalevitz et al, 2006;Satyal et al, 2000), by blocking proteasome mediated degradation (Bence et al, 2001;Bennett et al, 2005) or by inhibiting autophagy . Other models suggest that the aggregates can engage in aberrant interaction with cellular membranes leading to the formation of membrane pores (Lashuel et al, 2002) or they can disturb cellular ion homeostasis (Quist et al, 2005), may cause mitochondrial dysfunction and oxidative stress (Muller et al, 2010) (Figure 8).…”

Section: Prion Protein Extracellularmentioning

confidence: 99%

“…Several studies have documented a role of Htt in causing UPS impairment (Bence et al, 2001;Bennett et al, 2005;Venkatraman et al, 2004). More recently, it was shown that mutant Htt, whether aggregated or not, does not impair the 26S proteasome directly but it leads to the accumulation of ubiquitinated substrates which disrupts cellular proteostasis (Hipp et al, 2012).…”

Section: Vi5 Fluc-based Sensors Report On Proteostasis Collapse By mentioning

confidence: 99%

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Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Prion Protein Extracellularmentioning

confidence: 99%

Section: Vi5 Fluc-based Sensors Report On Proteostasis Collapse By mentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…Irreversibly misfolded proteins are toxic to the cell because they trap normal proteins in aggregates and they inhibit the proteasome-dependent protein degradation pathway (Holmberg et al, 2004;Schaffar et al, 2004;Bennett et al, 2005). Mutations that alter amino acid residues often cause protein misfolding, which leads to various diseases, including neurodegenerative disease (Barral et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, CCT was shown to inhibit protein aggregation and counteract the cytotoxicity of misfolded proteins (Behrends et al, 2006;Kitamura et al, 2006;Kubota et al, 2006;Tam et al, 2006). These observations indicate that molecular chaperones are indispensable for protecting cells against the pernicious effects of misfolded proteins.Irreversibly misfolded proteins are toxic to the cell because they trap normal proteins in aggregates and they inhibit the proteasome-dependent protein degradation pathway (Holmberg et al, 2004;Schaffar et al, 2004;Bennett et al, 2005). Mutations that alter amino acid residues often cause protein misfolding, which leads to various diseases, including neurodegenerative disease (Barral et al, 2004).…”

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confidence: 99%

MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination

Hirayama

Yamazaki²,

Kitamura³

et al. 2008

MBoC

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McKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease characterized by several developmental anomalies. Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder with pleiotropic symptoms. However, little is known about how MKKS mutations lead to disease. Here, we show that disease-causing mutants of MKKS are rapidly degraded via the ubiquitin-proteasome pathway in a manner dependent on HSC70 interacting protein (CHIP), a chaperone-dependent ubiquitin ligase. Although wild-type MKKS quickly shuttles between the centrosome and cytosol in living cells, the rapidly degraded mutants often fail to localize to the centrosome. Inhibition of proteasome functions causes MKKS mutants to form insoluble structures at the centrosome. CHIP and partner chaperones, including heat-shock protein (HSP)70/heat-shock cognate 70 and HSP90, strongly recognize MKKS mutants. Modest knockdown of CHIP by RNA interference moderately inhibited the degradation of MKKS mutants. These results indicate that the MKKS mutants have an abnormal conformation and that chaperone-dependent degradation mediated by CHIP is a key feature of MKKS/BBS diseases. INTRODUCTIONMcKusick-Kaufman syndrome (MKKS) is a recessively inherited human genetic disease predominantly characterized by developmental anomalies, including vaginal atresia with hydrometrocolpos, polydactyly, and congenital heart defects (McKusick et al., 1964). The MKKS gene encodes a 570-amino acid polypeptide with weak but significant similarity to group II chaperonins . Mutations in the MKKS gene also cause Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder characterized by obesity, retinal dystrophy, polydactyly, mental retardation, renal malformation, and hypogenitalism (Beales et al., 1999), and thus MKKS is also called BBS6. The MKKS mRNA is widely expressed in various tissues, including those affected by MKKS and BBS diseases . Although more than 10 mutations in the MKKS gene have been identified in patients (Beales et al., 2001;Slavotinek et al., 2002), little is known about how they cause MKKS and BBS.Twelve of the genes that are responsible for BBS (BBS1-12) have been identified so far, and the products of several of these genes have been suggested to be involved in intraflagellar transport in cilia and intracellular trafficking in the cytosol Badano et al., 2005;Beales, 2005;Blacque and Leroux, 2006). Cargo-carrying motors play crucial roles in intraflagellar and intracellular transport systems by bidirectionally moving on microtubules, and BBS4 interacts with the dynactin complex, which mediates interactions between cargoes and the dynein motor (Kim et al., 2004). Retrograde transport of melanosomes in zebrafish is slowed by knockdown of BBS2 or BBS4-8 (Yen et al., 2006), whereas mutations in Caenorhabditis elegans BBS7 and BBS8 cause delays in intraflagellar transport driven by kinesin motors (Ou et al., 2005). The Chlamydomonas homologue of BBS5 is essential for flagellum formation (Li et al., ...

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“…Interferon pathways could also be affected by expression of genes related to proteasome, immunoproteasome, and ubiquitin-mediated proteolysis in the 5-9 age group (Supplemental Table S3). These pathways are also involved in neurodegenerative movement disorders including Huntington's Disease (Bennett et al, 2005). B cell and antibody function may also be affected since there is down-regulation of precursor B cell immunoglobulin regions necessary for competent B cell receptor (antibody) rearrangement (e.g.…”

Section: Hypothesis Generation For Further Studymentioning

confidence: 99%

Age-related gene expression in Tourette syndrome

Lit

Enstrom

Sharp

et al. 2009

Journal of Psychiatric Research

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Because infection and immune responses have been implicated in the pathogenesis of Tourette Syndrome (TS), we hypothesized that children with TS would have altered gene expression in blood compared to controls. In addition, because TS symptoms in childhood vary with age, we tested whether gene expression changes that occur with age in TS differ from normal control children. Whole blood was obtained from 30 children and adolescents with TS and 28 healthy children and adolescents matched for age, race and gender. Gene expression (RNA) was assessed using whole genome Affymetrix microarrays. Age was analyzed as a continuous covariate and also stratified into three groups: 5-9 (common age for tic onset), 10-12 (when tics often peak), and 13-16 (tics may begin to wane). No global differences were found between TS and controls. However, expression of many genes and multiple pathways differed between TS and controls within each age group (5-9, 10-12, and 13-16), including genes involved in the immune-synapse, and proteasome-and ubiquitinmediated proteolysis pathways. Notably, across age strata, expression of interferon response, viral processing, Natural Killer and cytotoxic T-lymphocyte cell genes differed. Our findings suggest agerelated interferon, immune and protein degradation gene expression differences between TS and controls.

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Global Impairment of the Ubiquitin-Proteasome System by Nuclear or Cytoplasmic Protein Aggregates Precedes Inclusion Body Formation

Cited by 464 publications

References 56 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

MKKS Is a Centrosome-shuttling Protein Degraded by Disease-causing Mutations via CHIP-mediated Ubiquitination

Age-related gene expression in Tourette syndrome

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