NEDD1 stabilization regulated by hUTP14a and FBW7γ axis safeguards mitotic cell fate homeostasis

Accurate spindle formation is vital for mitotic progression and genomic DNA segregation, with γ-tubulin ring complex (γ-TuRC) mediating microtubule nucleation, and NEDD1 serving as its essential recruitment/anchoring adaptor. However, the mechanisms underlying the regulation of NEDD1 remain largely elusive. Here, we identify a pathway that controls NEDD1 stability during mitosis. hUTP14a relocates to the perichromosomal region at mitotic onset; its depletion causes mitotic catastrophe, impaired chromosomal congression, and reduced γ-tubulin recruitment around chromosomes. Mass spectrometry identifies NEDD1 as a critical hUTP14a-interacting partner during mitosis. hUTP14a protects NEDD1 from ubiquitin-mediated degradation. UbiBrowser 2.0 database prediction and validation experiments identify FBW7γ as an E3 ligase to promote NEDD1 K323 ubiquitination-mediated degradation, while hUTP14a facilitates FBW7γ degradation in a leucine-rich repeat (LRR)-dependent manner. The hUTP14a depletion-induced mitotic catastrophe is reversed by ectopic Flag-NEDD1-K323R but not wild-type Flag-NEDD1. Thus, NEDD1 is stabilized via hUTP14a-mediated FBW7γ degradation to safeguard mitotic cell fate.