| First Author | Fiume G | Year | 2012 |
| Journal | Nucleic Acids Res | Volume | 40 |
| Issue | 8 | Pages | 3548-62 |
| PubMed ID | 22187158 | Mgi Jnum | J:197732 |
| Mgi Id | MGI:5494386 | Doi | 10.1093/nar/gkr1224 |
| Citation | Fiume G, et al. (2012) Human immunodeficiency virus-1 Tat activates NF-kappaB via physical interaction with IkappaB-alpha and p65. Nucleic Acids Res 40(8):3548-62 |
| abstractText | Nuclear factor (NF)-kappaB is a master regulator of pro-inflammatory genes and is upregulated in human immunodeficiency virus 1 (HIV-1) infection. Mechanisms underlying the NF-kappaB 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-kappaB by hijacking the inhibitor IkappaB-alpha and by preventing the repressor binding to the NF-kappaB complex. Moreover, Tat associated with the p65 subunit of NF-kappaB and increased the p65 DNA-binding affinity and transcriptional activity. The arginine- and cysteine-rich domains of Tat were required for IkappaB-alpha and p65 association, respectively, and for sustaining the NF-kappaB activity. Among an array of NF-kappaB-responsive genes, Tat mostly activated the MIP-1alpha expression in a p65-dependent manner, and bound to the MIP-1alpha NF-kappaB enhancer thus promoting the recruitment of p65 with displacement of IkappaB-alpha; similar findings were obtained for the NF-kappaB-responsive genes CSF3, LTA, NFKBIA and TLR2. Our results support a novel mechanism of NF-kappaB activation via physical interaction of Tat with IkappaB-alpha and p65, and may contribute to further insights into the deregulation of the inflammatory response by HIV-1. |
