Caveolin-1 prevents palmitate-induced NF-κB signaling by inhibiting GPRC5B-phosphorylation

Abstract

Tyrosine phosphorylation of GPRC5B and phosphorylation-dependent recruitment of Fyn through the SH2 domain have been implicated in NF-κB activation and obesity-linked adipose inflammation. GPRC5B tightly associates with caveolin-1 (Cav1); however, the role of this interaction remains elusive. Here, we report that Cav1 reduces GPRC5B-mediated NF-κB signaling by blocking GPRC5B-phosphorylation. We demonstrate highly abundant tyrosine phosphorylation of GPRC5B is observed in Neuro2a cells lacking endogenous Cav1 expression. Reversely, exogenous expression of Cav1 in these cells inhibits GPRC5B-phosphorylation. Although GPRC5B lacks conventional caveolin-binding motif, cytoplasmic tail of GPRC5B directly interacts with the C-terminal domain of Cav1. The vacant scaffolding domain of Cav1 in the protein complex suggests a potential mechanism for blocking GPRC5B-phosphorylation by Cav1, because Fyn loses the activity by binding with Cav1-scaffolding domain. Enhanced GPRC5B-mediated NF-κB signaling in Cav1-deficient cells were observed under palmitate-induced metabolic stress. These results support Cav1 functions as a negative modulator for GPRC5B action.

Keywords: Caveolin-1; GPRC5B; Metabolic stress; NF-κB; Phosphorylation; Protein interaction.