Deubiquitinase USP8 regulates the spindle assembly checkpoint in oocytes

The spindle assembly checkpoint (SAC) is vital for preventing oocyte aneuploidy, a leading cause of female infertility, miscarriages, and trisomy syndromes. However, whether deubiquitination participates in SAC regulation remains unknown. Here, we reveal that the deubiquitinase USP8 acts as a SAC regulator to prevent aneuploid egg formation. Mechanistically, depletion of USP8 inactivates the SAC, accelerates meiotic progression, and causes abnormal spindle assembly and chromosome alignment, ultimately leading to aneuploidy. Intriguingly, we identify USP8 in oocytes as a previously unidentified interaction partner of BUB3, a key component of the SAC, and demonstrate that USP8 stabilizes BUB3 through its deubiquitinating activity. Moreover, exogenous BUB3 rescues the defects observed in USP8-depleted oocytes. Together, our findings not only clarify that deubiquitination participates in regulating the SAC in oocytes but also uncover a unique role for USP8 in controlling the SAC via its interaction with BUB3.