Molecular Recognition Research Center, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 02792, Korea.
Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG), Seoul National University, Gwanak-Ro 1, Gwanak-Gu, Seoul, 08826, Korea.
Nat Commun. 2018 Feb 15;9(1):688. doi: 10.1038/s41467-018-03107-0.
Although approximately 100 deubiquitinating enzymes (DUBs) are encoded in the human genome, very little is known about the DUBs that function in mitosis. Here, we demonstrate that DUB USP35 functions as a mitotic regulator by controlling the protein levels and downstream signaling of Aurora B and the depletion of USP35 eventually leads to several mitotic defects including cytokinesis failures. USP35 binds to and deubiquitinates Aurora B, and inhibits the APC-mediated proteasomal degradation of Aurora B, thus maintaining its steady-state levels during mitosis. In addition, the loss of USP35 decreases the phosphorylation of histone H3-Ser10, an Aurora B substrate. Finally, the transcription factor FoxM1 promotes the expression of USP35, as well as that of Aurora B, during the cell cycle. Our findings suggest that USP35 regulates the stability and function of Aurora B by blocking APC-induced proteasomal degradation, thereby controlling mitotic progression.
虽然人类基因组中大约编码了 100 种去泛素化酶（DUBs），但对于在有丝分裂中起作用的 DUBs 知之甚少。在这里，我们证明 DUB USP35 通过控制 Aurora B 的蛋白水平和下游信号转导来发挥有丝分裂调节剂的作用，USP35 的耗竭最终导致包括胞质分裂失败在内的多种有丝分裂缺陷。USP35 与 Aurora B 结合并使其去泛素化，并抑制 APC 介导的 Aurora B 的蛋白酶体降解，从而在有丝分裂过程中维持其稳定状态。此外，USP35 的缺失会降低 Aurora B 的底物组蛋白 H3-Ser10 的磷酸化水平。最后，转录因子 FoxM1 在细胞周期中促进 USP35 和 Aurora B 的表达。我们的研究结果表明，USP35 通过阻止 APC 诱导的蛋白酶体降解来调节 Aurora B 的稳定性和功能，从而控制有丝分裂进程。
