A ubiquitin-proteasome pathway degrades the inner nuclear membrane protein Bqt4 to maintain nuclear membrane homeostasis

Abstract

AbstractAberrant accumulation of inner nuclear membrane (INM) proteins has been associated with deformed nuclear morphology and certain mammalian diseases. However, the mechanisms by which INM homeostasis is maintained remain poorly understood. In this study, we explored the degradation mechanisms of the INM protein Bqt4 in the fission yeastSchizosaccharomyces pombe. We have previously shown that Bqt4 interacts with the transmembrane protein Bqt3 at the INM and is degraded in the absence of Bqt3. Here, we revealed that excess Bqt4 unassociated with Bqt3 was targeted for degradation by the ubiquitin-proteasome system localized in the nucleus and that Bqt3 antagonized this process. The degradation process involves the Doa10 E3 ligase complex at the INM. Bqt4 is a tail-anchored protein and extraction from the membrane by the Cdc48 complex is required for its degradation. The C-terminal transmembrane domain of Bqt4 is necessary and sufficient for proteasome-dependent protein degradation. Accumulation of Bqt4 at the INM impaired cell viability with nuclear envelope deformation, suggesting that the quantity control of Bqt4 plays an important role in nuclear membrane homeostasis.Summary statementThe appropriate level of the inner nuclear membrane protein Bqt4 is maintained by ubiquitin-proteasome-mediated degradation. Aberrant accumulation of Bqt4 disturbs the nuclear membrane homeostasis.