Protein VAC14 homolog, also known as ArPIKfyve, is a protein that in humans is encoded by the VAC14gene.
Functions and interactions
The content of phosphatidylinositol 3,5-bisphosphate in endosomal membranes changes dynamically with fission and fusion events that generate or absorb intracellular transport vesicles. The ArPIKfyve protein scaffolds a trimolecular complex to tightly regulate the level of PtdInsP2. Other components of this complex are the PtdInsP2-synthesizing enzyme PIKFYVE and the Sac1-domain-containing PtdInsP2 5-phosphatase Sac3, encoded by the human geneFIG4. VAC14 functions as an activator of PIKFYVE. Studies in VAC14 knockout mice indicate that, in addition to increasing the PtdInsP2-producing activity of PIKfyve, VAC14 also controls the steady-state levels of another rare phosphoinositide linked to PIKfyve enzyme activity – phosphatidylinositol 5-phosphate. In addition to the formation of the ternary complex with PIKfyve and Sac3, ArPIKfyve is engaged in a number of other interactions. ArPIKfyve forms a stable complex with the PtdInsP2-specific phosphatase Sac3, thereby protecting Sac3 from rapid degradation in the proteasome. ArPIKfyve forms a homooligomer through its carboxyl terminus. However, the number of monomers in the ArPIKfyve homooligomer, ArPIKfyve-Sac3 heterodimer or PIKfyve-ArPIKfyve-Sac3 heterotrimer is unknown. Human Vac14/ArPIKfyve also interacts with the PDZ domain of neuronal nitric oxide synthase but the functional significance of this interaction is still unclear. ArPIKfyve facilitates insulin-regulated GLUT4 translocation to the cell surface.
Lessons from VAC14 mouse models
VAC14 knock-out mice die at, or shortly after birth and exhibit massive neurodegeneration. Fibroblasts from these mice display ~50% lower levels of PtdInsP2 and PtdInsP. A spontaneous mouse VAC14-point mutation is associated with reduced life span, body size, enlarged brain ventricles, 50% decrease in PtdInsP2 levels, diluted pigmentation, tremor and impairedmotor function.
