SUMO ylation is required for PIPK 1γ‐driven keratinocyte migration and growth

PIPKIgamma, a key member of the type I phosphatidylinositol 4-phosphate kinase (PIPKI) family that regulates the spatial-temporal generation of PIP2, has been implicated in diverse biological processes including cell survival, cell polarity, and cell migration. An essential role of PIPKIgamma in tumor cells and nerve cells has been established in previous studies. However, the function and regulatory mechanism of PIPKIgamma remains incompletely understood. Here, we showed that PIPKIgamma can specifically associate with the SUMO-conjugating (E2) enzyme UBC9 and can be SUMOylated both in vivo and in vitro. We further identified that Lys-591 is the critical SUMO-acceptor site of PIPKIgamma and that SUMO conjugation at this site is required for PIPKIgamma-driven keratinocyte migration and growth. Mechanistically, SUMOylation deficiency significantly disrupts PIPKIgamma-mediated generation of intracellular PIP2, rather than the subcellular translocation and protein stability of PIPKIgamma. Our findings reveal that PIPKIgamma is a novel SUMOylation target and highlight the essential role of PIPKIgamma SUMOylation in human keratinocyte function, providing an important orientation for in-depth study of wound repair.