Myosin VI drives arrestin-independent internalization and signaling of GPCRs
Abstract G protein-coupled receptor (GPCR) endocytosis is canonically associated with β-arrestins. Here, we delineate a β-arrestin-independent endocytic pathway driven by the cytoskeletal motor, myosin VI. Myosin VI engages GIPC, an adaptor protein that binds a PDZ sequence motif present at the C-te...
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| Format: | Article |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55053-9 |
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| author | Nishaben M. Patel Léa Ripoll Chloe J. Peach Ning Ma Emily E. Blythe Nagarajan Vaidehi Nigel W. Bunnett Mark von Zastrow Sivaraj Sivaramakrishnan |
| author_facet | Nishaben M. Patel Léa Ripoll Chloe J. Peach Ning Ma Emily E. Blythe Nagarajan Vaidehi Nigel W. Bunnett Mark von Zastrow Sivaraj Sivaramakrishnan |
| author_sort | Nishaben M. Patel |
| collection | DOAJ |
| description | Abstract G protein-coupled receptor (GPCR) endocytosis is canonically associated with β-arrestins. Here, we delineate a β-arrestin-independent endocytic pathway driven by the cytoskeletal motor, myosin VI. Myosin VI engages GIPC, an adaptor protein that binds a PDZ sequence motif present at the C-terminus of several GPCRs. Using the D2 dopamine receptor (D2R) as a prototype, we find that myosin VI regulates receptor endocytosis, spatiotemporal localization, and signaling. We find that access to the D2R C-tail for myosin VI-driven internalization is controlled by an interaction between the C-tail and the third intracellular loop of the receptor. Agonist efficacy, co-factors, and GIPC expression modulate this interaction to tune agonist trafficking. Myosin VI is differentially regulated by distinct GPCR C-tails, suggesting a mechanism to shape spatiotemporal signaling profiles in different ligand and physiological contexts. Our biophysical and structural insights may advance orthogonal therapeutic strategies for targeting GPCRs through cytoskeletal motor proteins. |
| format | Article |
| id | doaj-art-3dee4150cd6f48cb81a29bb29098c782 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3dee4150cd6f48cb81a29bb29098c7822025-08-20T02:31:19ZengNature PortfolioNature Communications2041-17232024-12-0115111510.1038/s41467-024-55053-9Myosin VI drives arrestin-independent internalization and signaling of GPCRsNishaben M. Patel0Léa Ripoll1Chloe J. Peach2Ning Ma3Emily E. Blythe4Nagarajan Vaidehi5Nigel W. Bunnett6Mark von Zastrow7Sivaraj Sivaramakrishnan8Department of Genetics, Cell Biology and Development, University of MinnesotaDepartment of Psychiatry and Behavioral Sciences, University of California, San FranciscoDepartment of Molecular Pathobiology, New York UniversityIrell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of HopeDepartment of Psychiatry and Behavioral Sciences, University of California, San FranciscoIrell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of HopeDepartment of Molecular Pathobiology, New York UniversityDepartment of Psychiatry and Behavioral Sciences, University of California, San FranciscoDepartment of Genetics, Cell Biology and Development, University of MinnesotaAbstract G protein-coupled receptor (GPCR) endocytosis is canonically associated with β-arrestins. Here, we delineate a β-arrestin-independent endocytic pathway driven by the cytoskeletal motor, myosin VI. Myosin VI engages GIPC, an adaptor protein that binds a PDZ sequence motif present at the C-terminus of several GPCRs. Using the D2 dopamine receptor (D2R) as a prototype, we find that myosin VI regulates receptor endocytosis, spatiotemporal localization, and signaling. We find that access to the D2R C-tail for myosin VI-driven internalization is controlled by an interaction between the C-tail and the third intracellular loop of the receptor. Agonist efficacy, co-factors, and GIPC expression modulate this interaction to tune agonist trafficking. Myosin VI is differentially regulated by distinct GPCR C-tails, suggesting a mechanism to shape spatiotemporal signaling profiles in different ligand and physiological contexts. Our biophysical and structural insights may advance orthogonal therapeutic strategies for targeting GPCRs through cytoskeletal motor proteins.https://doi.org/10.1038/s41467-024-55053-9 |
| spellingShingle | Nishaben M. Patel Léa Ripoll Chloe J. Peach Ning Ma Emily E. Blythe Nagarajan Vaidehi Nigel W. Bunnett Mark von Zastrow Sivaraj Sivaramakrishnan Myosin VI drives arrestin-independent internalization and signaling of GPCRs Nature Communications |
| title | Myosin VI drives arrestin-independent internalization and signaling of GPCRs |
| title_full | Myosin VI drives arrestin-independent internalization and signaling of GPCRs |
| title_fullStr | Myosin VI drives arrestin-independent internalization and signaling of GPCRs |
| title_full_unstemmed | Myosin VI drives arrestin-independent internalization and signaling of GPCRs |
| title_short | Myosin VI drives arrestin-independent internalization and signaling of GPCRs |
| title_sort | myosin vi drives arrestin independent internalization and signaling of gpcrs |
| url | https://doi.org/10.1038/s41467-024-55053-9 |
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