NudC-like protein 2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90
NudC-like protein 2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90
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DOI：
10.1073/pnas.0914307107
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发表时间：
2010-02
期刊：
影响因子：
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通讯作者：
Yuehong Yang;Xiaoyi Yan;Yuqi Cai;Yiqing Lu;Jianmin Si;Tianhua Zhou
中科院分区：
文献类型：
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作者：
Yuehong Yang;Xiaoyi Yan;Yuqi Cai;Yiqing Lu;Jianmin Si;Tianhua Zhou
I型无脑畸形基因产物LIS 1是细胞质动力蛋白的关键调节因子，对细胞增殖、存活和神经元迁移至关重要。然而，对LIS 1的调控知之甚少。在这里，我们确定了一个以前未表征的哺乳动物同源曲霉NudC，NudCL 2（NudC样蛋白2），作为一个调节LIS 1。NudCL 2定位于间期的中心体，以及有丝分裂期间的纺锤体极和动粒，其模式类似于LIS 1和细胞质动力蛋白的定位。NudCL 2的耗尽使LIS 1不稳定，并导致类似于动力蛋白或LIS 1缺陷的表型。NudCL 2与LIS 1和Hsp 90复合并增强LIS 1和Hsp 90的相互作用。破坏LIS 1-Hsp 90与NudCL 2的C末端的相互作用或通过格尔德霉素抑制Hsp 90分子伴侣功能降低了LIS 1的稳定性。因此，我们的研究结果表明，NudCL 2调节LIS 1/动力蛋白途径稳定LIS 1与Hsp 90伴侣。这代表了哺乳动物细胞中LIS 1/动力蛋白调节的一种迄今未描述的机制。
The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability. Thus, our results suggest that NudCL2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90 chaperone. This represents a hitherto undescribed mechanism of the LIS1/dynein regulation in mammalian cells.