Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3499-504. doi: 10.1073/pnas.0914307107. Epub 2010 Feb 3.
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.
I 型无脑回畸形相关基因产物 LIS1 是细胞质动力蛋白的关键调节因子，对于细胞增殖、存活和神经元迁移至关重要。然而，对于 LIS1 的调控机制了解甚少。在这里，我们鉴定出一种以前未被表征的哺乳动物 Aspergillus NudC 同源物 NudCL2（NudC 样蛋白 2），作为 LIS1 的调节因子。NudCL2 在有丝分裂间期定位于中心体，在有丝分裂期间定位于纺锤体极和动粒，其定位模式与 LIS1 和细胞质动力蛋白的定位模式相似。NudCL2 的耗竭导致 LIS1 不稳定，并导致类似于动力蛋白或 LIS1 缺乏的表型。NudCL2 与 LIS1 和热休克蛋白 90（Hsp90）相互作用，并增强其相互作用。NudCL2 通过 C 末端与 LIS1-Hsp90 相互作用的破坏或格尔德霉素对 Hsp90 伴侣功能的抑制，降低了 LIS1 的稳定性。因此，我们的结果表明，NudCL2 通过与 Hsp90 伴侣一起稳定 LIS1 来调节 LIS1/动力蛋白途径。这代表了哺乳动物细胞中 LIS1/动力蛋白调节的一种迄今为止尚未描述的机制。
