β-Arrestin 2 is required for lysophosphatidic acid-induced NF-κB activation

Lysophosphatidic acid (LPA) is a bioactive phospholipid and binds to its receptors, a family of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and leads to activation of several transcription factors, including NF-kappa B Although LPA-induced signaling pathways have been intensively investigated, the molecular mechanism by which LPA activates NF-kappa B is not fully Defined. In this work, we found that beta-arrestin 2, but not beta-arrestin 1, is required for LPA-induced NF-kappa B activation and interlukin-6 expression. Mechanistically, we found that Rho-arrestin 2 associated with CARMA3, a scaffold protein that plays an essential role in GPCR-induced NF-kappa B activation, suggesting that beta-arrestin 2 may recruit CARMA3 to LPA receptors. Although beta-arrestin 2 deficiency did not affect LPA-induced IKK alpha/beta phosphorylation, it impaired LPA-induced IKK kinase activity, which is consistent with our previous findings that CARMA3 is required for IKK alpha/beta activation but not for the inducible phosphorylation of IKK alpha/beta. Together, our results provide the genetic evidence that beta-arrestin 2 serves as a positive regulator in NF-kappa B signaling pathway by connecting CARMA3 to GPCRs.