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

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. Turnover of ER proteins has been well characterized by the ER-associated protein degradation (ERAD) pathway, but very little is known about turnover of resident INM proteins. 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 enzyme Ubc7, but was independent of the known ERAD ubiquitin ligases Doa10 and Hrd1 as well as the recently discovered 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’s 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 degradation at the INM that coordinates nuclear morphogenesis and cell cycle progression.