%0 Journal Article %T HIV-1 Nef Hijacks Lck and Rac1 Endosomal Traffic To Dually Modulate Signaling-Mediated and Actin Cytoskeleton–Mediated T Cell Functions %+ Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology %+ Collège Doctoral %A del Río-Iñiguez, Iratxe %A Vázquez-Chávez, Elena %A Cuche, Céline %A Di Bartolo, Vincenzo %A Bouchet, Jérôme %A Alcover, Andres %Z This work was supported by grants from the Agence Nationale de Recherche sur le Syndrome d’Immunodéficience Acquise et les Hepatitis Virales (ANRS; Grant AO 2013-02 CSS1 1339/14673), Sidaction (Grant VIH20160721001), the Institut Pasteur, INSERM, and the People Programme (Marie Sklodowska-Curie Actions) of the European Union’s Seventh Framework Programme (Grant FP7/2007-2013 under the Research Executive Agency Grant Agreement 317057 HOMIN-ITN). The Photonic BioImaging UTechS microscopy facility at the Institut Pasteur is part of the France BioImaging infrastructure supported by Grant ANR-10-INSB-04-01, Investments for the Future. Individual funding was as follows: I.d.R.-I. obtained predoctoral funding from European Union Marie Curie Actions HOMIN-ITN (cited above), the Fondation pour la Recherche Médicale, and the ANRS. I.d.R.-I. is a scholar in the Pasteur-Paris University international doctoral program; E.V.-C. received postdoctoral funding from Sidaction; J.B. received postdoctoral funding from the ANRS, the Roux-Institut Pasteur, and Sidaction. %< avec comité de lecture %@ 0022-1767 %J Journal of Immunology %I Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists %V 201 %N 9 %P 2624 - 2640 %8 2018-11-01 %D 2018 %R 10.4049/jimmunol.1800372 %M 30282749 %Z Life Sciences [q-bio]/Immunology/Immunotherapy %Z Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]Journal articles %X Endosomal traffic of TCR and signaling molecules regulates immunological synapse formation and T cell activation. We recently showed that Rab11 endosomes regulate the subcellular localization of the tyrosine kinase Lck and of the GTPase Rac1 and control their functions in TCR signaling and actin cytoskeleton remodeling. HIV-1 infection of T cells alters their endosomal traffic, activation capacity, and actin cytoskeleton organization. The viral protein Nef is pivotal for these modifications. We hypothesized that HIV-1 Nef could jointly alter Lck and Rac1 endosomal traffic and concomitantly modulate their functions. In this study, we show that HIV-1 infection of human T cells sequesters both Lck and Rac1 in a pericentrosomal compartment in an Nef-dependent manner. Strikingly, the Nef-induced Lck compartment contains signaling-competent forms (phosphorylated on key Tyr residues) of Lck and some of its downstream effectors, TCRζ, ZAP70, SLP76, and Vav1, avoiding the proximal LAT adaptor. Importantly, Nef-induced concentration of signaling molecules was concomitant with the upregulation of several early and late T cell activation genes. Moreover, preventing the concentration of the Nef-induced Lck compartment by depleting the Rab11 effector FIP3 counteracted Nef-induced gene expression upregulation. In addition, Nef extensively sequesters Rac1 and downregulates Rac1-dependent actin cytoskeleton remodeling, thus reducing T cell spreading. Therefore, by modifying their endosomal traffic, Nef hijacks signaling and actin cytoskeleton regulators to dually modulate their functional outputs. Our data shed new light into the molecular mechanisms that modify T cell physiology during HIV-1 infection. %G English %2 https://pasteur.hal.science/pasteur-01907920/document %2 https://pasteur.hal.science/pasteur-01907920/file/Del%20Rio%20et%20al_J%20Immunol%202018.pdf %L pasteur-01907920 %U https://pasteur.hal.science/pasteur-01907920 %~ PASTEUR %~ OPENAIRE %~ SORBONNE-UNIVERSITE %~ SORBONNE-UNIV %~ SU-TI %~ ALLIANCE-SU %~ FRM