4.6 Article

HIV-1 Nef Hijacks Lck and Rac1 Endosomal Traffic To Dually Modulate Signaling-Mediated and Actin Cytoskeleton-Mediated T Cell Functions

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JOURNAL OF IMMUNOLOGY
卷 201, 期 9, 页码 2624-2640

出版社

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1800372

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资金

  1. Agence Nationale de Recherche sur le Syndrome d'Immunodeficience Acquise et les Hepatitis Virales (ANRS) [AO 2013-02 CSS1 1339/14673]
  2. Sidaction [VIH20160721001]
  3. Institut Pasteur
  4. INSERM
  5. People Programme (Marie Sklodowska-Curie Actions) of the European Union's Seventh Framework Programme [317057 HOMIN-ITN]
  6. Investments for the Future [ANR-10-INSB-04-01]
  7. European Union Marie Curie Actions HOMIN-ITN
  8. Fondation pour la Recherche Medicale
  9. ANRS
  10. Sidaction
  11. Roux-Institut Pasteur

向作者/读者索取更多资源

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 Racl 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, TC14, 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.

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