MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination
MKKS is a centrosome-shuttling protein degraded by disease-causing mutations via CHIP-mediated ubiquitination
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DOI：
10.1091/mbc.e07-07-0631
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发表时间：
2008-03-01
影响因子：
3.3
通讯作者：
Nagata, Kazuhiro
中科院分区：
文献类型：
--
作者：
Hirayama, Shoshiro;Yamazaki, Yuji;Nagata, Kazuhiro
McKusick-Kaufman综合征（MKKS）是一种以多种发育异常为特征的人类遗传性疾病。MKKS基因的突变也会导致Bardet-Biedl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，人们对MKKS突变如何导致疾病知之甚少。在这里，我们表明，致病突变体的MKKS迅速降解，通过泛素-蛋白酶体途径的方式依赖于HSC 70相互作用蛋白（CHIP），伴侣依赖性泛素连接酶。尽管野生型MKKS在活细胞中在中心体和胞质溶胶之间快速穿梭，但快速降解的突变体通常不能定位于中心体。蛋白酶体功能的抑制导致MKKS突变体在中心体形成不溶性结构。CHIP和伴侣分子伴侣，包括热休克蛋白（HSP）70/热休克同源70和HSP 90，强烈识别MKKS突变体。通过RNA干扰适度敲低CHIP适度抑制了MKKS突变体的降解。这些结果表明MKKS突变体具有异常构象，并且CHIP介导的伴侣依赖性降解是MKKS/BBS疾病的一个关键特征。
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.