Autotaxin facilitates selective LPA receptor signaling

Abstract

Autotaxin (ATX; ENPP2) produces the lipid mediator lysophosphatidic acid (LPA) that signals through disparate EDG (LPA1-3) and P2Y (LPA4-6) G protein-coupled receptors. ATX/LPA promote several (patho)physiological processes, including in pulmonary fibrosis, thus serving as attractive drug targets. However, it remains unclear if clinical outcome depends on how different ATX inhibitors modulate the ATX/LPA signaling axis. Here, we show that inhibitors binding to the ATX "tunnel" specifically abrogate key aspects of ATX/LPA signaling. We find that the tunnel is essential for signaling efficacy and dictates cellular responses independent of ATX catalytic activity, with a preference for activation of P2Y LPA receptors. These responses are abrogated by tunnel-binding inhibitors, such as ziritaxestat, but not by inhibitors that exclusively target the active site, as shown in primary lung fibroblasts and a murine model of radiation-induced pulmonary fibrosis. Our results uncover a receptor-selective signaling mechanism for ATX, implying clinical benefit for tunnel-targeting ATX inhibitors.

A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis

“…We have recently shown that mechanistic differences between type I and type IV inhibitors, rather than inhibitor potency in preventing the enzymatic hydrolysis of LPC to LPA alone, can lead to different physiological activity (preprint: Salgado‐Polo et al , 2022). Here, we set out to examine the effect of type IV inhibitor in liver disease models, as, despite the clear involvement of the ATX/LPA signaling pathway in liver diseases, inhibition of ATX has been underexplored in relevant liver disease models.…”