Abstract:
: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.
journal_name
Mol Biol Celljournal_title
Molecular biology of the cellauthors
Hirayama S,Yamazaki Y,Kitamura A,Oda Y,Morito D,Okawa K,Kimura H,Cyr DM,Kubota H,Nagata Kdoi
10.1091/mbc.e07-07-0631subject
Has Abstractpub_date
2008-03-01 00:00:00pages
899-911issue
3eissn
1059-1524issn
1939-4586pii
E07-07-0631journal_volume
19pub_type
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