IkappaB-alpha represses the transcriptional activity of the HIV-1 Tat transactivator by promoting its nuclear export.
The long terminal repeat of human immunodeficiency virus, type 1 (HIV-1) contains an NF-kappaB enhancer and is potently inhibited by IkappaB-alphaS32/36A, a proteolysis-resistant inhibitor of NF-kappaB transacting factors. The evidence that NF-kappaB is dispensable for HIV-1 expression raises the question of whether IkappaB-alpha represses the HIV-1 transcription by mechanisms distinct from NF-kappaB inhibition. Here, we report that IkappaB-alpha negatively regulates the HIV-1 expression and replication in an NF-kappaB-independent manner by directly binding to Tat, which results in the nuclear export and cytoplasmic sequestration of the viral transactivator. The sequence of IkappaB-alpha required for Tat inhibition spans from amino acids 72 to 287 and includes the nuclear localization signal, the carboxyl-terminal nuclear export signal, and the binding site for the arginine-rich domain of Tat. This novel mechanism of cross-talk between Tat and IkappaB-alpha provides further insights into the mechanisms of HIV-1 regulation and could assist in the development of novel strategies for AIDS therapy.
Puca
Antimina
A
Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
Fiume
Giuseppe
G
Palmieri
Camillo
C
Trimboli
Francesca
F
Olimpico
Francesco
F
Scala
Giuseppe
G
Quinto
Ileana
I
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014779:Virus Replication / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D019913:Nuclear Localization Signals; D054322:tat Gene Products, Human Immunodeficiency Virus; D000072000:NF-KappaB Inhibitor alpha