HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane.
J Biol Chem
; 295(15): 5163-5174, 2020 04 10.
Article
en En
| MEDLINE
| ID: mdl-32144207
ABSTRACT
The HIV-1 virulence factor Nef promotes high-titer viral replication, immune escape, and pathogenicity. Nef interacts with interleukin-2-inducible T-cell kinase (Itk) and Bruton's tyrosine kinase (Btk), two Tec-family kinases expressed in HIV-1 target cells (CD4 T cells and macrophages, respectively). Using a cell-based bimolecular fluorescence complementation assay, here we demonstrate that Nef recruits both Itk and Btk to the cell membrane and induces constitutive kinase activation in transfected 293T cells. Nef homodimerization-defective mutants retained their interaction with both kinases but failed to induce activation, supporting a role for Nef homodimer formation in the activation mechanism. HIV-1 infection up-regulates endogenous Itk activity in SupT1 T cells and donor-derived peripheral blood mononuclear cells. However, HIV-1 strains expressing Nef variants with mutations in the dimerization interface replicated poorly and were significantly attenuated in Itk activation. We conclude that direct activation of Itk and Btk by Nef at the membrane in HIV-infected cells may override normal immune receptor control of Tec-family kinase activity to enhance the viral life cycle.
Palabras clave
Bruton's tyrosine kinase (BTK); HIV-1 Nef; T-cell receptor (TCR); Tec-family kinase; bimolecular fluorescence complementation (BiFC); dimerization; human immunodeficiency virus (HIV); infectious disease; interleukin-2-inducible kinase (ITK); protein kinase; proteinprotein interaction; signal transduction
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Tirosina Quinasas
/
Infecciones por VIH
/
Membrana Celular
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VIH-1
/
Productos del Gen nef del Virus de la Inmunodeficiencia Humana
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Agammaglobulinemia Tirosina Quinasa
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2020
Tipo del documento:
Article