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HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane

The Journal of biological chemistry, 2020-04, Vol.295 (15), p.5163-5174 [Peer Reviewed Journal]

2020 © 2020 Li et al. ;2020 Li et al. ;2020 Li et al. 2020 Li et al. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA120.012536 ;PMID: 32144207

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Title:
HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane
Author: Li, Wing Fai ; Aryal, Manish ; Shu, Sherry T. ; Smithgall, Thomas E.
Subjects: Agammaglobulinaemia Tyrosine Kinase - genetics ; Agammaglobulinaemia Tyrosine Kinase - metabolism ; Antiviral Agents - pharmacology ; bimolecular fluorescence complementation (BiFC) ; Bruton's tyrosine kinase (BTK) ; Cell Membrane - metabolism ; dimerization ; HIV Infections - immunology ; HIV Infections - metabolism ; HIV Infections - virology ; HIV-1 - immunology ; HIV-1 Nef ; human immunodeficiency virus (HIV) ; Humans ; infectious disease ; interleukin-2-inducible kinase (ITK) ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - immunology ; Leukocytes, Mononuclear - virology ; nef Gene Products, Human Immunodeficiency Virus - chemistry ; nef Gene Products, Human Immunodeficiency Virus - genetics ; nef Gene Products, Human Immunodeficiency Virus - metabolism ; protein kinase ; Protein Multimerization ; Protein-Tyrosine Kinases - genetics ; Protein-Tyrosine Kinases - metabolism ; protein–protein interaction ; Signal Transduction ; Small Molecule Libraries - pharmacology ; T-cell receptor (TCR) ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - virology ; Tec-family kinase ; Virus Replication
Is Part Of: The Journal of biological chemistry, 2020-04, Vol.295 (15), p.5163-5174
Description: 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.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.RA120.012536
PMID: 32144207
Source: Open Access: PubMed Central
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HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane

2020 © 2020 Li et al. ;2020 Li et al. ;2020 Li et al. 2020 Li et al. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA120.012536 ;PMID: 32144207

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