Ubiquitin-like protein 4A (Ubl4A) is a small protein encoded by a “housekeeping” gene that locates on the X chromosome. As a multi-functional... Show moreUbiquitin-like protein 4A (Ubl4A) is a small protein encoded by a “housekeeping” gene that locates on the X chromosome. As a multi-functional protein, it has roles in a variety of cellular events including anti-tumorigenesis, response to DNA damage, inhibiting the fusion between autophagosome and lysosome, and docking of the tail-anchored proteins to the endoplasmic reticulum. We have previously reported that the newborns from Ubl4A-deficient mice had a high rate of mortality due to defect of AKT-dependent glucose metabolism. At the molecular level, Ubl4A directly binds with the actin related protein (Arp) 2/3 complex to accelerate the building up of the actin branching network, which further promotes the translocation and activation of the Akt, a key kinase for multiple cellular processes, from the cytosol to the plasma membrane.In further exploration of the molecular basis of Ubl4A in cell survival, here, we demonstrated that Ubl4A is critical for mitochondrial fusion and cell survival under nutrient depletion. In WT (wild-type) cells, the association of Ubl4A and the Arp2/3 complex serves as a primed “pool” of the actin branching network near mitochondria and enables mitochondria to fuse quickly for energy conservation upon starvation insult. However, such a “ready-to-go pool” of mitochondria was significantly decreased in the Ubl4A-deficient cells. As the result, the mitochondria became fragmentated, exhibited decreased trans-membrane potential, and accumulated ROS (reactive oxygen species), consequently, initiated mitochondria-mediated apoptosis.
In this study, we also observed that Ubl4A-deficient mice displayed type II diabetic phenotype under a high-fat diet feeding. The preliminary results showed that these Ubl4A-deficient mice were more sensitive to glucose intolerance than their WT littermates, most likely owing to a delay in glucose uptake, and/or insulin secretion, both of which require the Arp2/3-actin branching network. We speculated that Ubl4A might be involved in cellular vesicle formation and/or secretion, but further investigation is needed to approve this hypothesis. Taken together, these findings provide a novel function of Ubl4A and further insight into the multi-functional roles of Ubl4A in mammalian cells, as well as the molecular basis for understanding the clinical relevance of Ubl4A in related human diseases. Show less
