Journal
EMBO REPORTS
Volume 22, Issue 4, Pages -Publisher
WILEY
DOI: 10.15252/embr.202052196
Keywords
ARHGAP45; cell migration; chemotaxis; GTPase‐ activating protein; lymphocyte
Categories
Funding
- CNRS, INSERM
- European Union [787300]
- MSDAVENIR Fund
- Investissement d'Avenir program PHENOMIN (French National Infrastructure for mouse Phenogenomics) [ANR-10-INBS-07]
- National Natural Science Foundation of China [81471595, 32070898, 81901573]
- 111 project [D20036]
- Fondation pour la Recherche Medicale
- Agence Nationale de la Recherche [RECRUTE: ANR-15-CE15-0022, ILIAAD: ANR-18-CE09-0029]
- Excellence Initiative of Aix-Marseille University-A*MIDEX
- French Investissements d'Avenir program
- IBISA (Infrastructures Biologie Sante et Agronomie)
- Plan Cancer
- Canceropole PACA
- Region Sud Provence-Alpes-Cote d'Azur
- Institut Paoli-Calmettes
- Centre de Recherche en Cancerologie de Marseille
- Plateforme Technologie Aix-Marseille
- Fonds Europeen de Developpement Regional
- European Research Council (ERC) [787300] Funding Source: European Research Council (ERC)
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The study reveals that ARHGAP45 GAP plays a key role in the lifecycle of T and B cells, controlling cell deformability and motility which affect the entry of cells into lymph nodes and engraftment in the bone marrow.
T and B cells continually recirculate between blood and secondary lymphoid organs. To promote their trans-endothelial migration (TEM), chemokine receptors control the activity of RHO family small GTPases in part via GTPase-activating proteins (GAPs). T and B cells express several RHO-GAPs, the function of most of which remains unknown. The ARHGAP45 GAP is predominantly expressed in hematopoietic cells. To define its in vivo function, we describe two mouse models where ARHGAP45 is ablated systemically or selectively in T cells. We combine their analysis with affinity purification coupled to mass spectrometry to determine the ARHGAP45 interactome in T cells and with time-lapse and reflection interference contrast microscopy to assess the role of ARGHAP45 in T-cell polarization and motility. We demonstrate that ARHGAP45 regulates naive T-cell deformability and motility. Under physiological conditions, ARHGAP45 controls the entry of naive T and B cells into lymph nodes whereas under competitive repopulation it further regulates hematopoietic progenitor cell engraftment in the bone marrow, and T-cell progenitor thymus seeding. Therefore, the ARGHAP45 GAP controls multiple key steps in the life of T and B cells.
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