Inefficient degradation of truncated polyglutamine proteins by the proteasome

Holmberg, Carina I.; Staniszewski, Kristine E; Mensah, Kwame; Matouschek, Andreas T; Morimoto, Richard I.

doi:10.1038/sj.emboj.7600426

Cited by 256 publications

(225 citation statements)

References 37 publications

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“…Aggregate size and morphology was likewise unaltered (Fig. 2b) similar to what has been reported previously 20,21 . Consistent with the visual increase in aggregate-containing cell numbers was an increase in htt protein detected by the filter trap assay for 7.5-fold (Fig.…”

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confidence: 87%

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Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state

et al. 2006

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Proteins with expanded polyQ repeats are associated with at least nine neurodegenerative disorders including ataxins 1 and 3, Kennedy's disease, and Huntington's disease (HD) 1,2 . These diseases are dominantly inherited and although the polyQ-containing proteins are expressed widely in the brain, they result in selective neuronal death. There is a significant and striking correlation between the length of the polyQ repeat and pathology; longer repeats result in earlier onset and more severe symptoms with the threshold of approximately 40 glutamine residues. In the case of HD, for example, expanded polyQ in huntingtin (htt) protein causes disease 3,4 . A characteristic of the polyQ diseases is the appearance of neuronal inclusions that are formed by aggregation of the polyQ proteins with other cellular proteins 5,6 . This has led to the "toxic gain-of-function" hypothesis that essential proteins can be sequestered, which 3 over time leads to cellular dysgenesis. The expression of polyQ can cause other metastable proteins to lose functionality, and in turn these proteins amplify the toxicity of polyQ by enhancing overall aggregation 7 . Self-aggregation of polyQ proteins has been proposed to be mediated by association of parallel β-sheet structures 8 . However, the intrinsic in vivo events leading to the aggregation of polyQ proteins remain poorly understood.Protein misfolding is a natural consequence of protein biogenesis. To combat cytotoxicity that results from the accumulation of misfolded proteins, all cells express molecular chaperones that are essential for the productive folding of proteins 9,10 . Molecular chaperones are of several classes; for example, Hsp70/J-domain proteins interact with unfolded or partially folded proteins in concert with co-chaperones, while the chaperone machines of the chaperonin (Hsp60) family form cage-like structures that sequester non-native states of proteins 11 . The chaperonin containing t-complex polypeptide 1 (CCT)/t-complex polypeptide 1 ring complex (TRiC) is a member of chaperonin family 12 that facilitates the folding of proteins in the eukaryotic cytosol upon ATP hydrolysis 13,14 . CCT shows a weak but significant homology to E. coli GroEL and forms a hexadecamer double-troidal complex composed of eight different subunits 15,16 . Substrate proteins are captured in the cavity, and released after folding is completed 17 . Approximately 10% of newly-synthesized proteins have been proposed to be recognized by CCT.Recently, in a genome-wide screen to identify modifier genes for polyQ aggregation in C. elegans, approximately 200 genes were found to be required for the prevention of polyQ aggregation 18 . This included the genes encoding two Hsp70s, one J-protein, and six CCT subunits. These observations suggested a 4 role of CCT in preventing polyQ aggregation. We show here in mammalian cells that CCT has a key protective role against the toxicity of htt/polyQ and affects aggregation process at the soluble stage. In the context of our recent in vitro data showing that ...

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supporting

confidence: 87%

“…1b). The CCT complex was also 20 . Upon CCTζ depletion there was a 2.5-fold increase in aggregate containing cells (Fig.…”

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confidence: 99%

Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state

et al. 2006

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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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“…Nowadays, evidence has been provided that polyQ is a poor substrate for eukaryotic proteasome [73] . A long polyQ stretch or a stable polyQ polar zipper hairpin [74][75][76] may enter the catalytic core of the proteasome and occupy or block access to the proteolytic sites for an extended period of time.…”

Section: Parkinson's Disease and Ups Parkinson's Disease (Pd)mentioning

confidence: 99%

The roles of the proteasome pathway in signal transduction and neurodegenerative diseases

2008

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There are two degradation systems in mammalian cells, autophagy/lysosomal pathway and ubiquitin-proteasome pathway. Proteasome is consist of multiple protein subunits and plays important roles in degradation of short-lived cellular proteins. Recent studies reveal that proteasomal degradation system is also involved in signal transduction and regulation of various cellular functions. Dysfunction or dysregulation of proteasomal function may thus be an important pathogenic mechanism in certain neurological disorders. This paper reviews the biological functions of proteasome in signal transduction and its potential roles in neurodegenerative diseases.

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Inefficient degradation of truncated polyglutamine proteins by the proteasome

Cited by 256 publications

References 37 publications

Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state

Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state

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

The roles of the proteasome pathway in signal transduction and neurodegenerative diseases

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