The L279P Mutation of Nuclear Distribution Gene C (NudC) Influences Its Chaperone Activity and Lissencephaly Protein 1 (LIS1) Stability
The L279P Mutation of Nuclear Distribution Gene C (NudC) Influences Its Chaperone Activity and Lissencephaly Protein 1 (LIS1) Stability
复制标题
核分布基因 C (NudC) L279P 突变影响其伴侣活性和无脑畸形蛋白 1 (LIS1) 稳定性
DOI：
10.1074/jbc.m110.105494
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发表时间：
2010-09-24
影响因子：
4.8
通讯作者：
Zhou, Tianhua
中科院分区：
文献类型：
--
作者：
Zhu, Xiao-Jing;Liu, Xunyan;Zhou, Tianhua
LIS 1基因在经典无脑畸形中突变，在细胞质动力蛋白调节、有丝分裂和细胞迁移中起重要作用。然而，LIS 1（lissencephaly protein 1）蛋白的调控在很大程度上仍然未知。在构巢曲霉中的遗传研究已经发现，Nud（核分布）途径参与调节细胞质动力蛋白复合物，并且nudC基因（L146 P）中的温度敏感性突变极大地降低了NudF（LIS 1的曲霉直向同源物）的蛋白水平。在这里，我们发现L146在裸曲霉及其侧翼区是高度保守的进化过程中。人NudC（L279 P）中的类似突变明显导致LIS 1减少和与LIS 1下调相似的细胞表型。为了探索潜在的机制，我们发现含有p23结构域的蛋白NudC与分子伴侣Hsp 90结合，Hsp 90也与LIS 1相关。格尔德霉素或根赤霉素抑制Hsp 90分子伴侣功能导致LIS 1水平降低。Hsp 90的异位表达部分逆转了由NudC-L279 P过表达引起的LIS 1降解。此外，NudC被发现调节Hsp 90的ATP酶活性，这是由L279 P突变抑制。有趣的是，NudC本身被证明具有伴侣功能，这也被L279 P突变抑制。总之，这些数据表明，NudC可能参与调节LIS 1的稳定性，其伴侣功能。
LIS1, a gene mutated in classical lissencephaly, plays essential roles in cytoplasmic dynein regulation, mitosis and cell migration. However, the regulation of LIS1 (lissencephaly protein 1) protein remains largely unknown. Genetic studies in Aspergillus nidulans have uncovered that the Nud (nuclear distribution) pathway is involved in the regulation of cytoplasmic dynein complex and a temperature-sensitive mutation in the nudC gene (L146P) greatly reduces the protein levels of NudF, an Aspergillus ortholog of LIS1. Here, we showed that L146 in Aspergillus NudC and its flanking region were highly conservative during evolution. The similar mutation in human NudC (L279P) obviously led to reduced LIS1 and cellular phenotypes similar to those of LIS1 down-regulation. To explore the underlying mechanism, we found that the p23 domain-containing protein NudC bound to the molecular chaperone Hsp90, which is also associated with LIS1. Inhibition of Hsp90 chaperone function by either geldanamycin or radicicol resulted in a decrease in LIS1 levels. Ectopic expression of Hsp90 partially reversed the degradation of LIS1 caused by overexpression of NudC-L279P. Furthermore, NudC was found to regulate the ATPase activity of Hsp90, which was repressed by the mutation of L279P. Interestingly, NudC itself was shown to possess a chaperone function, which also was suppressed by the L279P mutation. Together, these data suggest that NudC may be involved in the regulation of LIS1 stability by its chaperone function.