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

• Published in: Journal of cellular biochemistry 2021-08, Vol.122 (8), p.827-834
• Main Authors: Taleb, Sarah J, Wei, Jianxin, Mialki, Rachel K, Dong, Su, Li, Yanhui, Zhao, Jing, Zhao, Yutong
• Format: Article
• Language: English
• Subjects: Animals; blocking peptide; Cell Line; Cell migration; Degradation; Disruption; E3 ubiquitin ligase; Epithelial cells; Epithelium; Extracellular signal-regulated kinase; Fibrosis; Gene expression; GPCR; Humans; Inflammation; Kinases; LPA1; Lung diseases; Lysophosphatidic acid; Lysophospholipids - genetics; Lysophospholipids - metabolism; MAP Kinase Signaling System; Matrix metalloproteinases; Metalloproteinase; Mice; Nedd4 Ubiquitin Protein Ligases - genetics; Nedd4 Ubiquitin Protein Ligases - metabolism; Peptides; Phosphorylation; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitors; Proteolysis; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Receptors; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - metabolism; Signaling; Stability; Therapeutic targets; Ubiquitin; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-protein ligase; Ubiquitination
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.29919

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. LPA1 plays a critical role in the pathogenesis of human diseases. LPA1 stability has been shown to be regulated by the ubiquitin‐proteasome system. We found that a blocking peptide stabilizes LPA1 through disruption of LPA1 interaction with its E3 ubiquitin ligase Nedd4L.