The anaphase-promoting complex regulates the degradation of the inner nuclear membrane protein Mps3 in budding yeast

The nucleus is enclosed by the inner nuclear membrane (INM) and the outer nuclear membrane (ONM). While the ONM is continuous with the endoplasmic reticulum (ER), the INM is independent and separates the nucleoplasm from the ER lumen. To maintain INM homeostasis, proteins mislocalized to the INM are degraded by the ER-associated protein degradation (ERAD) pathway. However, the mechanism for turnover of resident INM proteins is less clear. Here we show that the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase, regulates the degradation of Mps3, a conserved integral protein of the INM. Turnover of Mps3 requires the ubiquitin-conjugating enzymes Ubc7 and Ubc6, but not the three known ERAD ubiquitin ligases, Doa10, Hrd1, and the Asi1-Asi3 complex. Using a genetic approach, we have found that Cdh1, a coactivator of APC/C, modulates Mps3 stability. APC/C controls Mps3 degradation through Mps3 N-terminus, which resides in the nucleoplasm and possesses two putative APC/C-dependent destruction motifs. Accumulation of Mps3 at the INM impairs nuclear morphological changes and cell division. Our findings therefore reveal an unexpected mechanism of APC/C-mediated protein quality control at the INM that coordinates nuclear morphogenesis and cell-cycle progression.