Hirayama Shoshiro, Yamazaki Yuji, Kitamura Akira, Oda Yukako, Morito Daisuke, Okawa Katsuya, Kimura Hiroshi, Cyr Douglas M, Kubota Hiroshi, Nagata Kazuhiro
Department of Molecular and Cellular Biolog, Kyoto University, Kyoto 606-8397, Japan.
Mol Biol Cell. 2008 Mar;19(3):899-911. doi: 10.1091/mbc.e07-07-0631. Epub 2007 Dec 19.
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.
麦库西克 - 考夫曼综合征（MKKS）是一种隐性遗传的人类遗传病，其特征为多种发育异常。MKKS基因突变还会导致巴德 - 比德尔综合征（BBS），这是一种具有多效性症状的遗传异质性疾病。然而，关于MKKS突变如何导致疾病，人们了解甚少。在此，我们表明，MKKS的致病突变体通过泛素 - 蛋白酶体途径迅速降解，其方式依赖于HSC70相互作用蛋白（CHIP），一种伴侣蛋白依赖性泛素连接酶。尽管野生型MKKS在活细胞中能在中心体和细胞质之间快速穿梭，但迅速降解的突变体常常无法定位于中心体。蛋白酶体功能的抑制会导致MKKS突变体在中心体形成不溶性结构。CHIP及其伴侣分子伴侣，包括热休克蛋白（HSP）70/热休克同源蛋白70和HSP90，能强烈识别MKKS突变体。通过RNA干扰适度敲低CHIP会适度抑制MKKS突变体的降解。这些结果表明，MKKS突变体具有异常构象，且由CHIP介导的伴侣蛋白依赖性降解是MKKS/BBS疾病的关键特征。
