SUMOylation is required for PIPK1γ-driven keratinocyte migration and growth

PIPKIγ, 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 PIPKIγ in tumor cells and nerve cells has been established in previous studies. However, the function and regulatory mechanism of PIPKIγ remains incompletely understood. Here, we showed that PIPKIγ 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 PIPKIγ and that SUMO conjugation at this site is required for PIPKIγ-driven keratinocyte migration and growth. Mechanistically, SUMOylation deficiency significantly disrupts PIPKIγ-mediated generation of intracellular PIP2, rather than the subcellular translocation and protein stability of PIPKIγ. Our findings reveal that PIPKIγ is a novel SUMOylation target and highlight the essential role of PIPKIγ SUMOylation in human keratinocyte function, providing an important orientation for in-depth study of wound repair.