O-GlcNAcylation of the intellectual disability protein DDX3X exerts proteostatic cell cycle control
O-GlcNAcylation is an evolutionary conserved post-translational modification implicated in neurodevelopment. Missense variants of O-GlcNAc transferase (OGT) are causal for the intellectual disability syndrome OGT Congenital Disorder of Glycosylation (OGT-CDG). The observation of microcephaly in OGT-CDG patients suggests that dysregulation of the cell cycle and aberrant neurogenesis may contribute to disease aetiology. Here, we identify Ser584 O-GlcNAcylation of DDX3X, a known intellectual disability and microcephaly associated protein, as a key regulator of G1/S-phase transition, inhibiting proteasome-dependent degradation of DDX3X. DDX3X levels are reduced in a mouse model of OGT-CDG, alongside the DDX3X-target gene and synaptogenic regulator cyclin E1. These data reveal how a single DDX3X O-GlcNAc site exerts control of the cell cycle and highlights dysregulation of DDX3X-dependent translation, and concomitant impairments in cortical neurogenesis, as a possible pathway disrupted in OGT-CDG.