Human T-cell leukemia virus type 1 Tax modulates interferon-alpha signal transduction through competitive usage of the coactivator CBP/p300.
We describe here Tax protein of human T-cell leukemia virus type 1 (HTLV-1) as an interferon (IFN)-alpha antagonist counteracting the transactivation function of IFN-stimulated gene factor 3 (ISGF3). Co-expression of Tax, but not the Tax mutant unable to bind to CBP, significantly inhibited the reporter gene expression directed by IFN-stimulated regulatory elements, despite that the formation of DNA-binding ISGF3 complex was unaffected. Gene activation induced by STAT2 transcription domain was also inhibited by expression of Tax. Furthermore, Tax-mediated transcriptional inhibition was reversed by overexpression of p300. These observations indicate that Tax interferes with IFN-alpha-induced JAK-STAT pathway by competition with STAT2 for CBP/p300 binding. Consistently, GST pull-down assay showed that Tax dose-dependently inhibited binding of STAT2 to p300. This study suggests that Tax may prevent IFN-alpha from exerting its antiviral, antiproliferative and proapoptotic effects, thereby contributing to persistent viral infection and HTLV-1-associated oncogenesis.
Zhang
Jing
J
Research and Development Center, FUSO Pharmaceutical Industries, LTD., 2-3-30 Morinomiya, Joto-ku, Osaka 536-8523, Japan. j-zhang@fuso-pharm.co.jp
Yamada
Osamu
O
Kawagishi
Kenji
K
Araki
Hiromasa
H
Yamaoka
Shoji
S
Hattori
Toshio
T
Shimotohno
Kunitada
K
D001483:Base Sequence; D001667:Binding, Competitive; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D016356:Gene Products, tax / Q000235:genetics / Q000502:physiology*; D016355:Genes, pX; D015490:HTLV-I Infections / Q000209:etiology; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019169:Jurkat Cells; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
D017931:DNA Primers; D016356:Gene Products, tax; D050832:Interferon-Stimulated Gene Factor 3; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; C514970:tax protein, Human T-lymphotrophic virus 1; D050882:CREB-Binding Protein; C494363:CREBBP protein, human