Human immunodeficiency virus-1 Tat activates NF-κB via physical interaction with IκB-α and p65
Open Access
- 19 December 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 40 (8), 3548-3562
- https://doi.org/10.1093/nar/gkr1224
Abstract
Nuclear factor (NF)-κB is a master regulator of pro-inflammatory genes and is upregulated in human immunodeficiency virus 1 (HIV-1) infection. Mechanisms underlying the NF-κB deregulation by HIV-1 are relevant for immune dysfunction in AIDS. We report that in single round HIV-1 infection, or single-pulse PMA stimulation, the HIV-1 Tat transactivator activated NF-κB by hijacking the inhibitor IκB-α and by preventing the repressor binding to the NF-κB complex. Moreover, Tat associated with the p65 subunit of NF-κB and increased the p65 DNA-binding affinity and transcriptional activity. The arginine- and cysteine-rich domains of Tat were required for IκB-α and p65 association, respectively, and for sustaining the NF-κB activity. Among an array of NF-κB-responsive genes, Tat mostly activated the MIP-1α expression in a p65-dependent manner, and bound to the MIP-1α NF-κB enhancer thus promoting the recruitment of p65 with displacement of IκB-α; similar findings were obtained for the NF-κB-responsive genes CSF3 , LTA , NFKBIA and TLR2 . Our results support a novel mechanism of NF-κB activation via physical interaction of Tat with IκB-α and p65, and may contribute to further insights into the deregulation of the inflammatory response by HIV-1.Keywords
This publication has 96 references indexed in Scilit:
- Structural and functional insights into IκB-α/HIV-1 Tat interactionBiochimie, 2011
- β‐Chemokine production by neural and glial progenitor cells is enhanced by HIV‐1 Tat: effects on microglial migrationJournal of Neurochemistry, 2010
- A Coat of Many Colors: Neuroimmune Crosstalk in Human Immunodeficiency Virus InfectionNeuron, 2009
- Microarray Analysis of Lymphatic Tissue Reveals Stage-Specific, Gene Expression Signatures in HIV-1 InfectionThe Journal of Immunology, 2009
- HIV gp120 Induces, NF-κB Dependent, HIV Replication that Requires Procaspase 8PLOS ONE, 2009
- Emerging Concepts in the Immunopathogenesis of AIDSAnnual Review of Medicine, 2009
- Encoding NF-κB temporal control in response to TNF: distinct roles for the negative regulators IκBα and A20Genes & Development, 2008
- Human Immunodeficiency Virus Type 1 Tat Protein Inhibits the SIRT1 Deacetylase and Induces T Cell HyperactivationCell Host & Microbe, 2008
- De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signallingNature, 2004
- Induction of Rapid and Extensive β-Chemokine Synthesis in Macrophages by Human Immunodeficiency Virus Type 1 and gp120, Independently of Their Coreceptor PhenotypeJournal of Virology, 2001