A blocking peptide stabilizes lysophosphatidic acid receptor 1 and promotes lysophosphatidic acid‐induced cellular responses

Abstract

G protein‐coupled receptors regulate a variety of cellular responses and have been considered as therapeutic targets for human diseases. Lysophosphatidic acid receptor 1 (LPA1) is a receptor for bioactive lysophospholipid, LPA. LPA/LPA1‐mediated signaling contributes to inflammatory and fibrotic responses in lung diseases; thus understanding regulation of LPA1 stability is important for modulating LPA/LPA1 signaling. Our previous study has shown that LPA1 is degraded in the Nedd4 like (Nedd4L) E3 ubiquitin ligase‐mediated ubiquitin‐proteasome system. In the current study, we attempt to identify a peptide that stabilizes LPA1 through disrupting LPA1 association with Nedd4L. LPA treatment induces both endogenous and overexpressed LPA1 degradation, which is attenuated by a proteasome inhibitor, suggesting that LPA1 is degraded in the proteasome. LPA increases phosphorylation of extracellular signal‐regulated kinase 1/2 (Erk1/2) and I‐κB kinase in lung epithelial cells, and this effect is promoted by overexpression of a peptide (P1) that mimics C‐terminal of LPA1. P1, not a control peptide, attenuates LPA‐induced LPA1 ubiquitination and degradation, suggesting that P1 stabilizes LPA1. Further, P1 diminishes Nedd4L‐mediated degradation of LPA1 and Nedd4L/LPA1 association. In addition to increasing LPA1 signaling, P1 enhances LPA‐induced cell migration and gene expression of Elafin, matrix metallopeptidase 1, and serpin family B member 2 in lung epithelial cells. These data suggest that disruption of LPA1 interaction with Nedd4L by P1 increases LPA1 stability and LPA/LPA1 signaling.

Extracellular Lipids in the Lung and Their Role in Pulmonary Fibrosis

“…Mice lacking LPA receptor 1 exhibit a rapidly observable default in alveolarization [ 129 ]. In alveolar epithelial MLE12 cells, the stabilization of the LPA receptor 1 increases cell migration and ERK signaling ( Figure 2 ) [ 130 ]. Furthermore, the administration of an LPA antagonist consistently diminishes bleomycin-induced fibrosis by interfering with the activation of myofibroblasts [ 127 ].…”

Targeting GPCRs to treat cardiac fibrosis

“…The lysophospholipid receptor group is a member of the GPCR family of integral membrane proteins essential for lipid signaling ( 50 ). Lysophosphatidic acid (LPA) and its G protein-coupled receptor (LPA1) contribute to fibrosis progression ( 51 ). LPA1 is highly expressed on human primary fibroblasts, which predominantly couples to Gαq/11, Gαi/o, and Gα12/13 proteins ( 52 ).…”