The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-B
The chemokine receptor CXCR3 plays a critical role in immune cell recruitment and activation. CXCR3 exists as two main isoforms, CXCR3-A and CXCR3-B, resulting from alternative splicing. Although the two isoforms differ only by the presence of an N-terminal extension in CXCR3-B, they have been attri...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.868579/full |
| _version_ | 1811239652048240640 |
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| author | Giulia D’Uonnolo Giulia D’Uonnolo Nathan Reynders Nathan Reynders Max Meyrath Dayana Abboud Tomasz Uchański Toon Laeremans Brian F. Volkman Bassam Janji Julien Hanson Julien Hanson Martyna Szpakowska Martyna Szpakowska Andy Chevigné |
| author_facet | Giulia D’Uonnolo Giulia D’Uonnolo Nathan Reynders Nathan Reynders Max Meyrath Dayana Abboud Tomasz Uchański Toon Laeremans Brian F. Volkman Bassam Janji Julien Hanson Julien Hanson Martyna Szpakowska Martyna Szpakowska Andy Chevigné |
| author_sort | Giulia D’Uonnolo |
| collection | DOAJ |
| description | The chemokine receptor CXCR3 plays a critical role in immune cell recruitment and activation. CXCR3 exists as two main isoforms, CXCR3-A and CXCR3-B, resulting from alternative splicing. Although the two isoforms differ only by the presence of an N-terminal extension in CXCR3-B, they have been attributed divergent functional effects on cell migration and proliferation. CXCR3-B is the more enigmatic isoform and the mechanisms underlying its function and signaling remain elusive. We therefore undertook an in-depth cellular and molecular comparative study of CXCR3-A and CXCR3-B, investigating their activation at different levels of the signaling cascades, including G protein coupling, β-arrestin recruitment and modulation of secondary messengers as well as their downstream gene response elements. We also compared the subcellular localization of the two isoforms and their trafficking under resting and stimulated conditions along with their ability to internalize CXCR3-related chemokines. Here, we show that the N-terminal extension of CXCR3-B drastically affects receptor features, modifying its cellular localization and preventing G protein coupling, while preserving β-arrestin recruitment and chemokine uptake capacities. Moreover, we demonstrate that gradual truncation of the N terminus leads to progressive recovery of surface expression and G protein coupling. Our study clarifies the molecular basis underlying the divergent effects of CXCR3 isoforms, and emphasizes the β-arrestin-bias and the atypical nature of CXCR3-B. |
| first_indexed | 2024-04-12T13:04:58Z |
| format | Article |
| id | doaj.art-97a267f9626b47b594598c4e259d2560 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T13:04:58Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-97a267f9626b47b594598c4e259d25602022-12-22T03:32:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.868579868579The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-BGiulia D’Uonnolo0Giulia D’Uonnolo1Nathan Reynders2Nathan Reynders3Max Meyrath4Dayana Abboud5Tomasz Uchański6Toon Laeremans7Brian F. Volkman8Bassam Janji9Julien Hanson10Julien Hanson11Martyna Szpakowska12Martyna Szpakowska13Andy Chevigné14Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, LuxembourgFaculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgImmuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, LuxembourgFaculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, LuxembourgImmuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, LuxembourgLaboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, BelgiumImmuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, LuxembourgConfo Therapeutics, Ghent, BelgiumDepartment of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United StatesTumor Immunotherapy and Microenvironment, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, LuxembourgLaboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, BelgiumLaboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, BelgiumImmuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, LuxembourgTumor Immunotherapy and Microenvironment, Department of Oncology, Luxembourg Institute of Health, Luxembourg City, LuxembourgImmuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, LuxembourgThe chemokine receptor CXCR3 plays a critical role in immune cell recruitment and activation. CXCR3 exists as two main isoforms, CXCR3-A and CXCR3-B, resulting from alternative splicing. Although the two isoforms differ only by the presence of an N-terminal extension in CXCR3-B, they have been attributed divergent functional effects on cell migration and proliferation. CXCR3-B is the more enigmatic isoform and the mechanisms underlying its function and signaling remain elusive. We therefore undertook an in-depth cellular and molecular comparative study of CXCR3-A and CXCR3-B, investigating their activation at different levels of the signaling cascades, including G protein coupling, β-arrestin recruitment and modulation of secondary messengers as well as their downstream gene response elements. We also compared the subcellular localization of the two isoforms and their trafficking under resting and stimulated conditions along with their ability to internalize CXCR3-related chemokines. Here, we show that the N-terminal extension of CXCR3-B drastically affects receptor features, modifying its cellular localization and preventing G protein coupling, while preserving β-arrestin recruitment and chemokine uptake capacities. Moreover, we demonstrate that gradual truncation of the N terminus leads to progressive recovery of surface expression and G protein coupling. Our study clarifies the molecular basis underlying the divergent effects of CXCR3 isoforms, and emphasizes the β-arrestin-bias and the atypical nature of CXCR3-B.https://www.frontiersin.org/articles/10.3389/fimmu.2022.868579/fullACKR3ACKR2CXCR3BCXCL11/I-TACCXCL10/IP-10arrestin |
| spellingShingle | Giulia D’Uonnolo Giulia D’Uonnolo Nathan Reynders Nathan Reynders Max Meyrath Dayana Abboud Tomasz Uchański Toon Laeremans Brian F. Volkman Bassam Janji Julien Hanson Julien Hanson Martyna Szpakowska Martyna Szpakowska Andy Chevigné The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-B Frontiers in Immunology ACKR3 ACKR2 CXCR3B CXCL11/I-TAC CXCL10/IP-10 arrestin |
| title | The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-B |
| title_full | The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-B |
| title_fullStr | The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-B |
| title_full_unstemmed | The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-B |
| title_short | The Extended N-Terminal Domain Confers Atypical Chemokine Receptor Properties to CXCR3-B |
| title_sort | extended n terminal domain confers atypical chemokine receptor properties to cxcr3 b |
| topic | ACKR3 ACKR2 CXCR3B CXCL11/I-TAC CXCL10/IP-10 arrestin |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.868579/full |
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