Department of Cell Biology and the Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
Cell Mol Life Sci. 2019 Jan;76(2):381-395. doi: 10.1007/s00018-018-2957-y. Epub 2018 Oct 27.
Sister chromatid cohesion plays a key role in ensuring precise chromosome segregation during mitosis, which is mediated by the multisubunit cohesin complex. However, the molecular regulation of cohesin subunits stability remains unclear. Here, we show that NudCL2 (NudC-like protein 2) is essential for the stability of cohesin subunits by regulating Hsp90 ATPase activity in mammalian cells. Depletion of NudCL2 induces mitotic defects and premature sister chromatid separation and destabilizes cohesin subunits that interact with NudCL2. Similar defects are also observed upon inhibition of Hsp90 ATPase activity. Interestingly, ectopic expression of Hsp90 efficiently rescues the protein instability and functional deficiency of cohesin induced by NudCL2 depletion, but not vice versa. Moreover, NudCL2 not only binds to Hsp90, but also significantly modulates Hsp90 ATPase activity and promotes the chaperone function of Hsp90. Taken together, these data suggest that NudCL2 is a previously undescribed Hsp90 cochaperone to modulate sister chromatid cohesion by stabilizing cohesin subunits, providing a hitherto unrecognized mechanism that is crucial for faithful chromosome segregation during mitosis.
姐妹染色单体黏合在有丝分裂过程中确保精确的染色体分离中起着关键作用，这是由多亚基黏合复合物介导的。然而，黏合蛋白亚基稳定性的分子调控仍不清楚。在这里，我们发现 NudCL2（NudC 样蛋白 2）通过调节哺乳动物细胞中的 Hsp90 ATP 酶活性，对黏合蛋白亚基的稳定性是必需的。NudCL2 的耗竭会诱导有丝分裂缺陷和过早的姐妹染色单体分离，并使与 NudCL2 相互作用的黏合蛋白亚基不稳定。类似的缺陷也在抑制 Hsp90 ATP 酶活性时观察到。有趣的是，Hsp90 的异位表达可有效地挽救由 NudCL2 耗竭引起的黏合蛋白的不稳定性和功能缺陷，但反之则不行。此外，NudCL2 不仅与 Hsp90 结合，而且还显著调节 Hsp90 ATP 酶活性，并促进 Hsp90 的伴侣功能。总之，这些数据表明，NudCL2 是一种以前未被描述的 Hsp90 共伴侣，通过稳定黏合蛋白亚基来调节姐妹染色单体黏合，为有丝分裂过程中忠实的染色体分离提供了一个迄今未被认识的机制。
