RGS2 facilitates trophoblast function through a loop with the Hippo pathway and ubiquitination of CTGF

The regulator of G-protein signaling 2 (RGS2) plays a key role during pregnancy, whose dysregulation is closely associated with the progression of gestational disorders such as preeclampsia (PE). Therefore, investigating the downstream mechanisms regarding to RGS2-mediated biological events in trophoblasts would provide a better understanding of maintenance and progression of pregnancy. The present study describes the roles and underlying mechanisms of a regulation loop between RGS2 and the Hippo pathway in human trophoblasts, and additionally clarify that RGS2 independently mediates Connective tissue growth factor (CTGF) protein degradation by promoting its ubiquitination. At the molecular level, the ectopic expression of RGS2 deactivates the Hippo signaling but destabilizes CTGF by the Dual-specificity phosphatase 1(DUSP1)-Itchy E3 ubiquitin protein ligase (ITCH)-mediated ubiquitination of CTGF. Reciprocally, as a transcriptional co-activator, TAZ transactivates RGS2 through binding to and activating CREB. Consistently, the results could be verified in transgenic mouse placentas. Our results therefore identify the critical role of the RGS2-Hippo loop in regulating physiological function of trophoblasts during gestation.