Septin-associated PIPKIγ splice variants drive centralspindlin association with the midbody via PI(4,5)P2

Abstract

SummaryMammalian cytokinesis critically depends on the phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] which serves as docking site for crucial components of the cytokinetic machinery at the plasma membrane. PI(4,5)P2supports several stages of cytokinesis, including actomyosin ring assembly and constriction, membrane tethering of spindle microtubules, and midbody organization. How these various activities of PI(4,5)P2and the underlying mechanisms of local PI(4,5)P2synthesis are orchestrated in space and time has remained elusive. Here, we identify a pivotal role of septin-binding splice variants of PIPKIγ that couple nanoscale PI(4,5)P2synthesis at the ingressing cleavage furrow to late midbody formation. Depletion of PIPKIγ isoforms causes multinucleation and perturbs anillin and septin deposition at the intercellular bridge and at the midbody. These defects are rescued by wild-type kinase, but not by septin binding-deficient or catalytically inactive PIPKIγ variants. We further show that both, septins and PIPKIγ form a complex with centralspindlin, and thereby facilitate the recruitment of centralspindlin to the midbody. Taken together, our findings establish septin-associated PIPKIγ isoforms as key regulators of midbody organization that act through generating a local pool of PI4,5P2required for centralspindlin recruitment and maintenance at the midbody, and for septin association with microtubules.