ArticleThe Journal of biological chemistry2014
The accessory factor Nef links HIV-1 to Tec/Btk kinases in an Src homology 3 domain-dependent manner.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 33 citations in OpenAlex.
- Trial
- HIV-1 Nef inhibits the JAK/STAT signaling pathway by inducing proteasomal degradation of STAT1.PloS one · 2026Article
- HIV-1 Nef Uses a Conserved Pocket to Recruit the N-Terminal Cytoplasmic Tail of Serinc3.Viruses · 2025Article
- Nef defect attenuates HIV viremia and immune dysregulation in the bone marrow-liver-thymus-spleen (BLTS) humanized mouse model.Virology · 2024Article
- The HIV-1 protein Nef activates the Tec family kinase Btk by stabilizing an intermolecular SH3-SH2 domain interaction.Science signaling · 2022Article
- Inhibitors of HIV-1 Nef-Mediated Activation of the Myeloid Src-Family Kinase Hck Block HIV-1 Replication in Macrophages and Disrupt MHC-I Downregulation.ACS infectious diseases · 2022Article
- Evolutionary plasticity of SH3 domain binding by Nef proteins of the HIV-1/SIVcpz lentiviral lineage.PLoS pathogens · 2021Article
- Targeting ITK signaling for T cell-mediated diseases.iScience · 2021Review
- Visualization of Host Cell Kinase Activation by Viral Proteins Using GFP Fluorescence Complementation and Immunofluorescence Microscopy.Bio-protocol · 2021Article
- Synergy and allostery in ligand binding by HIV-1 Nef.The Biochemical journal · 2021Article
- Nef homodimers down-regulate SERINC5 by AP-2-mediated endocytosis to promote HIV-1 infectivity.The Journal of biological chemistry · 2020Article
- Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes.The Journal of biological chemistry · 2020Review
- HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane.The Journal of biological chemistry · 2020Article
- Tight-Binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-Mediated MHC-I Downregulation.ACS infectious diseases · 2020Article
- SIX3 and SIX6 interact with GEMININ via C-terminal regions.Biochemistry and biophysics reports · 2019Article
- Effects of BTK signalling in pathogenic microorganism infections.Journal of cellular and molecular medicine · 2019Review
- CD4AIDS research and human retroviruses · 2018Review
- IL-2 Inducible Kinase ITK is Critical for HIV-1 Infection of Jurkat T-cells.Scientific reports · 2018Article
- Remodeling of HIV-1 Nef Structure by Src-Family Kinase Binding.Journal of molecular biology · 2018Article
- A single β-octyl glucoside molecule induces HIV-1 Nef dimer formation in the absence of partner protein binding.PloS one · 2018Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The HIV-1 Nef virulence factor interacts with multiple host cell-signaling proteins. Nef binds to the Src homology 3 domains of Src family kinases, resulting in kinase activation important for viral infectivity, replication, and MHC-I down-regulation. Itk and other Tec family kinases are also present in HIV target cells, and Itk has been linked to HIV-1 infectivity and replication. However, the molecular mechanism linking Itk to HIV-1 is unknown. In this study, we explored the interaction of Nef with Tec family kinases using a cell-based bimolecular fluorescence complementation assay. In this approach, interaction of Nef with a partner kinase juxtaposes nonfluorescent YFP fragments fused to the C terminus of each protein, resulting in YFP complementation and a bright fluorescent signal. Using bimolecular fluorescence complementation, we observed that Nef interacts with the Tec family members Bmx, Btk, and Itk but not Tec or Txk. Interaction with Nef occurs through the kinase Src homology 3 domains and localizes to the plasma membrane. Allelic variants of Nef from all major HIV-1 subtypes interacted strongly with Itk in this assay, demonstrating the highly conserved nature of this interaction. A selective small molecule inhibitor of Itk kinase activity (BMS-509744) potently blocked wild-type HIV-1 infectivity and replication, but not that of a Nef-defective mutant. Nef induced constitutive Itk activation in transfected cells that was sensitive to inhibitor treatment. Taken together, these results provide the first evidence that Nef interacts with cytoplasmic tyrosine kinases of the Tec family and suggest that Nef provides a mechanistic link between HIV-1 and Itk signaling in the viral life cycle.
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