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Vol. 19, Issue 3, 899-911, March 2008

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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, Hiroshi Kimura, Douglas M. Cyr, Hiroshi Kubota^*,||, and Kazuhiro Nagata^*,||

*Department of Molecular and Cellular Biology and ^||Core Research for Evolutional Science and Technology/Japan Science and Technology Agency, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan; Biomolecular Characterization Unit and Nuclear Function and Dynamics Unit, Horizontal Medical Research Organization, School of Medicine, Kyoto University, Kyoto 606-8501, Japan; and Department of Cell and Developmental Biology and UNC Cystic Fibrosis Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599

Submitted July 3, 2007; Revised November 21, 2007; Accepted December 10, 2007
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 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.

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

Abbreviations used: BBS, Bardet–Biedl syndrome; CCT, chaperonin containing t-complex polypeptide 1; CHIP, carboxy terminus of HSC70 interacting protein; ER, endoplasmic reticulum; FRAP, fluorescence recover after photobleaching; FLIP, fluorescence loss in photobleaching; HSP60, 60-kDa heat-shock protein.; MKKS, McKusick–Kaufman syndrome.