The Short-Chain Fatty Acid Receptor GPR43 Modulates YAP/TAZ via RhoA
Bi-Oh Park, Seong Heon Kim, Jong-Hwan Kim, Seon‐Young Kim, Byoung Chul Park, Sang‐Bae Han, Sung Goo Park, Jeong‐Hoon Kim, Sunhong Kim
Abstract
GPR43 (also known as FFAR2 or FFA2) is a G-protein-coupled receptor primarily expressed in immune cells , enteroendocrine cells and adipocytes that recognizes short-chain fatty acids, such as acetate, propionate , and butyrate , likely to be implicated in innate immunity and host energy homeostasis . Activated GPR43 suppresses the cAMP level and induces Ca 2+ flux via coupling to Gα i and Gα q families, respectively. Additionally, GPR43 is reported to facilitate phosphorylation of ERK through G-protein-dependent pathways and interacts with β-arrestin 2 to inhibit NF-κB signaling. However, other G-protein-dependent and independent signaling pathways involving GPR43 remain to be established. Here, we have demonstrated that GPR43 augments Rho GTPase signaling. Acetate and a synthetic agonist effectively activated RhoA and stabilized YAP/TAZ transcriptional coactivators through interactions of GPR43 with Gα q/11 and Gα 12/13 . Acetate-induced nuclear accumulation of YAP was blocked by a GPR43-specific inverse agonist . The target genes induced by YAP/TAZ were further regulated by GPR43. Moreover, in THP-1–derived M1-like macrophage cells, the Rho-YAP/TAZ pathway was activated by acetate and a synthetic agonist. Our collective findings suggest that GPR43 acts as a mediator of the Rho-YAP/TAZ pathway.