A Small Housekeeping Gene with a Big “Heart”

Ubiquitin-like protein 4A (Ubl4A) is a housekeeping gene at X chromosome. Currently, the function of Ubl4A in mammals is largely unknown. We found that either overexpression or knockdown of Ubl4A promoted cell death in a cell culture system. Using an in vivo genetic knockout system, we found that Ubl4A knockout mice displayed a high neonatal mortality and had a defect in glycogen synthesis, which is mainly controlled by a key protein kinase Akt. Loss of Ubl4A resulted in the impairment of insulin-induced Akt translocation to the plasma membrane, an essential step for Akt activation. We demonstrated that Ubl4A directly interacted with actin-related protein 2/3 (Arp2/3) complex, and further accelerated Arp2/3 complex-dependent actin branching, thereby bringing Akt to proximity into the plasma membrane for activation. Furthermore, we showed that Ubl4A-mediated actin branching also played important roles in other cellular activities, such as formations of lamellipodia and filopodia, macrophage phagocytosis, wound healing, and neutrophil chemotaxis. These findings offer new insights into the roles of Ubl4A in cellular function and a molecular basis for treatment of related human diseases.