title: Clathrin regulates lymphocyte migration by driving actin accumulation at the cellular leading edge.
abstract: Lymphocyte migration, which is essential for effective immune responses, belongs to the so-called amoeboid migration. The lymphocyte migration is up to 100 times faster than between mesenchymal and epithelial cell types. Migrating lymphocytes are highly polarized in three well-defined structural and functional zones: uropod, medial zone, and leading edge (LE). The actiomyosin-dependent driving force moves forward the uropod, whereas massive actin rearrangements protruding the cell membrane are observed at the LE. These actin rearrangements resemble those observed at the immunological synapse driven by clathrin, a protein normally involved in endocytic processes. Here, we used cell lines as well as primary lymphocytes to demonstrate that clathrin and clathrin adaptors colocalize with actin at the LE of migrating lymphocytes, but not in other cellular zones that accumulate both clathrin and actin. Moreover, clathrin and clathrin adaptors, including Hrs, the clathrin adaptor for multivesicular bodies, drive local actin accumulation at the LE. Clathrin recruitment at the LE resulted necessary for a complete cell polarization and further lymphocyte migration in both 2D and 3D migration models. Therefore, clathrin, including the clathrin population associated to internal vesicles, controls lymphocyte migration by regulating actin rearrangements occurring at the LE.
authors.affiliation: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Department of Molecular & Cellular Biology, Madrid, Spain.|Instituto de Investigación Sanitaria Princesa, Hospital de Santa Cristina, Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ramírez-Santiago
authors.affiliation: Instituto de Investigación Sanitaria Princesa, Hospital de la Princesa, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Robles-Valero
authors.affiliation: Instituto de Investigación Sanitaria Princesa, Hospital de la Princesa, Madrid, Spain.
authors.forename: Giulia
authors.initials: G
authors.lastname: Morlino
authors.affiliation: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Department of Molecular & Cellular Biology, Madrid, Spain.|Instituto de Investigación Sanitaria Princesa, Hospital de Santa Cristina, Madrid, Spain.
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Cruz-Adalia
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pérez-Martínez
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Department of Macromolecular Structures, Madrid, Spain.
authors.forename: Airen
authors.initials: A
authors.lastname: Zaldivar
authors.affiliation: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Department of Molecular & Cellular Biology, Madrid, Spain.|Instituto de Investigación Sanitaria Princesa, Hospital de Santa Cristina, Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Torres-Torresano
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Department of Macromolecular Structures, Madrid, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Chichón
authors.affiliation: ALBA Synchrotron Light Source, MISTRAL Beamline-Experiments Division, Cerdanyola del Vallès, Barcelona, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sorrentino
authors.affiliation: ALBA Synchrotron Light Source, MISTRAL Beamline-Experiments Division, Cerdanyola del Vallès, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Pereiro
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Department of Macromolecular Structures, Madrid, Spain.|Unidad Asociada CNB (CSIC)-Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA Nanociencia), Cantoblanco, Madrid, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Carrascosa
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Megías
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Department of Macromolecular Structures, Madrid, Spain.
authors.forename: Carlos Oscar S
authors.initials: CO
authors.lastname: Sorzano
authors.affiliation: Instituto de Investigación Sanitaria Princesa, Hospital de la Princesa, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.affiliation: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Department of Molecular & Cellular Biology, Madrid, Spain. eveiga@cnb.csic.es.|Instituto de Investigación Sanitaria Princesa, Hospital de Santa Cristina, Madrid, Spain. eveiga@cnb.csic.es.
authors.forename: Esteban
authors.initials: E
authors.lastname: Veiga
mesh_terms: D000199:Actins / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity; D002966:Clathrin / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006801:Humans; D054992:Immunological Synapses; D019169:Jurkat Cells; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000502:physiology*; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D000199:Actins; D002966:Clathrin; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate
keywords: Cellular immunology; Cytoskeleton; Lymphocyte migration