A Phosphoinositide switch required for exit from cell division: PI3K-C2α in the regulation of cytokinetic abscission

Phosphoinositides define topologically unique membrane domains controlling the reversible recruitment of cytosolic proteins. Abscission is a spatiotemporally regulated process terminating mitosis that requires an ESCRT-dependent control of membrane remodeling at the cleavage site. We demonstrated that impairment in PI(4)P to PI(3,4)P2 conversion at midbody resulted in delayed cell division due to altered ESCRT machinery assembly. Mechanistically, PI3K-C2α produced PI(3,4)P2 at midbody by converting PI(4)P synthetized by PI4KA. Local PI(3,4)P2 synthesis triggered the recruitment of ESCRT-II to the midbody thus allowing proper cell division completing abscission. Patients with homologous loss-of-function mutations in PIK3C2A display syndromic features reminiscent of defective cell growth and premature aging including cataract. Concomitantly, defective phosphoinositide conversion at midbody detected in patient-derived fibroblasts was associated with cytokinetic failure and senescence. We used a zebrafish model of pik3c2a deficiency to link loss of PI3K-C2α cytokinetic regulation to impaired cell cycle progression. As human patients, homozygous zebrafish carrying nonsense mutations in pik3c2a spontaneously developed premature cataract. Acute loss of PI3K-C2α in fish embryos altered cell division stalling lens epithelial cells in cytokinesis and resulting in anticipated terminal differentiation, impaired fiber transition and senescence. Analogously, mice carrying truncating mutation in PIK3C2A showed similar lenticular alterations, highlighting that cytokinetic role of PI3K-C2α is conserved and its dysregulation results in defective cell growth, cell cycle exit and premature aging.