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MBC in Press, published online ahead of print December 19, 2007
Mol. Biol. Cell 10.1091/mbc.E07-07-0631

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Submitted on July 3, 2007
Revised on November 21, 2007
Accepted on December 10, 2007

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

Shoshiro Hirayama,* Yuji Yamazaki,* Akira Kitamura,* Yukako Oda,* Daisuke Morito,* Katsuya Okawa,{dagger} Hiroshi Kimura,{ddagger} Douglas M. Cyr,{sect} Hiroshi Kubota,*|| and Kazuhiro Nagata*||

*Department of Molecular and Cellular Biology and ||CREST/JST, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan; {dagger}Biomolecular Characterization Unit and {ddagger}Nuclear Function and Dynamics Unit, HMRO, School of Medicine, Kyoto University, Kyoto 606-8501, Japan; {sect}Department of Cell and Developmental Biology and UNC Cystic Fibrosis Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599

Monitoring Editor: Jeffrey Brodsky

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 CHIP, a chaperone-dependent ubiquitin ligase. While 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 HSP70/HSC70 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.

Address correspondence to: Hiroshi Kubota (hkubota{at}frontier.kyoto-u.ac.jp)






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