Fbxo30 Regulates Mammopoiesis by Targeting the Bipolar Mitotic Kinesin Eg5

•Fbxo30 is identified as the E3 ligase for bipolar mitotic kinesin Eg5•Deletion or shRNA silencing of Fbxo30 increases Eg5 and disrupts mitosis•Germline deletion of Fbxo30 disrupts normal mammopoiesis

SummaryFbxo30 is an orphan member of the F-box protein family with no known substrate or function. Here we report that, while Fbxo30−/− mice exhibit normal development, growth, lifespan, and fertility, the females fail to nurture their offspring as a result of defective mammopoiesis. Mass spectrometry analysis of Fbxo30-associated proteins revealed that Fbxo30 specifically interacts with the bipolar spindle kinesin EG5 (encoded by Kif11). As a result, Fbxo30 targets Eg5 for ubiquitinylation and controls its oscillation during the cell cycle. Correlated with EG5 dysregulation, Fbxo30−/− mammary epithelial cells exhibit multiple defects in centrosome homeostasis, mitotic spindle formation, and proliferation. Effects on proliferation, centrosome homeostasis, and mammopoiesis in the Fbxo30−/− mice were rescued through normalization of Eg5 activity using shRNA and/or an EG5 inhibitor. Our data reveal the Fbxo30-Eg5 interaction as a critical checkpoint in mammopoiesis and a critical role for ubiquitinylation-regulated Eg5 oscillation in the cell cycle.

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