Tyrosine phosphorylation of S1PR1 leads to chaperone BiP-mediated import to the endoplasmic reticulum
| Autor: | Jacob Matsche, Mumtaz Anwar, Ruhul Amin, Vijay Avin Balaji Ragunathrao, Andrei V. Karginov, Dolly Mehta, Gary C.H. Mo, Yulia Komarova, Richard D. Minshall |
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| Rok vydání: | 2020 |
| Předmět: |
Receptor recycling
macromolecular substances Biology Endoplasmic Reticulum Receptors G-Protein-Coupled chemistry.chemical_compound Cytosol Humans Phosphorylation Endoplasmic Reticulum Chaperone BiP Sphingosine-1-Phosphate Receptors S1PR1 G protein-coupled receptor Inflammation Tumor Necrosis Factor-alpha Endoplasmic reticulum Endothelial Cells ER retention Tyrosine phosphorylation Cell Biology Endocytosis Cell biology chemistry Proteolysis Tyrosine Signal transduction |
| Zdroj: | The Journal of cell biology. 220(12) |
| ISSN: | 1540-8140 |
| Popis: | Cell surface G protein–coupled receptors (GPCRs), upon agonist binding, undergo serine–threonine phosphorylation, leading to either receptor recycling or degradation. Here, we show a new fate of GPCRs, exemplified by ER retention of sphingosine-1-phosphate receptor 1 (S1PR1). We show that S1P phosphorylates S1PR1 on tyrosine residue Y143, which is associated with recruitment of activated BiP from the ER into the cytosol. BiP then interacts with endocytosed Y143-S1PR1 and delivers it into the ER. In contrast to WT-S1PR1, which is recycled and stabilizes the endothelial barrier, phosphomimicking S1PR1 (Y143D-S1PR1) is retained by BiP in the ER and increases cytosolic Ca2+ and disrupts barrier function. Intriguingly, a proinflammatory, but non-GPCR agonist, TNF-α, also triggered barrier-disruptive signaling by promoting S1PR1 phosphorylation on Y143 and its import into ER via BiP. BiP depletion restored Y143D-S1PR1 expression on the endothelial cell surface and rescued canonical receptor functions. Findings identify Y143-phosphorylated S1PR1 as a potential target for prevention of endothelial barrier breakdown under inflammatory conditions. |
| Databáze: | OpenAIRE |
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