WDR26 Functions as a Scaffolding Protein to Promote Gβγ-mediated Phospholipase C β2 (PLCβ2) Activation in Leukocytes

We have recently identified WDR26 as a novel WD40 repeat protein that binds G beta gamma and promotes G beta gamma signaling during leukocyte migration. Here, we have determined the mechanism by which WDR26 enhances G beta gamma-mediated phospholipase C beta 2 (PLC beta 2) activation in leukocytes. We show that WDR26 not only directly bound G beta gamma but also PLC beta 2. The binding sites of WDR26 and PLC beta 2 on G beta(1)gamma(2) were overlapping but not identical. WDR26 used the same domains for binding G beta gamma and PLC beta but still formed a signaling complex with G beta gamma and PLC beta 2 probably due to the fact that WDR26 formed a higher order oligomer through its Lis homology and C-terminal to LisH (LisH-CTLH) and WD40 domains. Additional studies indicated that the formation of higher order oligomers was required for WDR26 to promote PLC beta 2 interaction with and activation by G beta gamma. Moreover, WDR26 was required for PLC beta 2 translocation from the cytosol to the membrane in polarized leukocytes, and the translocation of PLC beta 2 was sufficient to cause partial activation of PLC beta 2. Collectively, our data indicate that WDR26 functions as a scaffolding protein to promote PLC beta 2 membrane translocation and interaction with G beta gamma, thereby enhancing PLC beta 2 activation in leukocytes. These findings have identified a novel mechanism of regulating G beta gamma signaling through a scaffolding protein.