Human T-cell leukemia virus type 1 Tax modulates interferon-α signal transduction through competitive usage of the coactivator CBP/p300

Abstract

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.

Oncogenic Human T-Cell Lymphotropic Virus Type 1 Tax Suppression of Primary Innate Immune Signaling Pathways

“…For example, our data indicate that, at higher concentrations, Tax also inhibits activation of type I IFN by activated IRF3/7, presumably by competition for transcription cofactors such as CBP/p300 (56).…”

Stromal Cell-Mediated Suppression of Human T-Cell Leukemia Virus Type 1 Expression In Vitro and In Vivo by Type I Interferon

“…Earlier studies indicated suppression of HTLV-1 expression by type I IFNs in vitro (25), and favorable clinical effects of a combination therapy of IFN-␣ and zidovudine for ATL (6). A recent report indicated that overexpression of HTLV-1 Tax inhibited the effects of type I IFN signals by competing with CBP/p300 (36). This may partly explain why the suppressive effect of stromal cells was weak on MT-2 cells (Fig.…”

Human T Cell Leukemia Virus Type 1 Tax Inhibits Innate Antiviral Signaling via NF-κB-Dependent Induction of SOCS1

“…HTLV-1 blocked IFN-␣-mediated induction of ISGs by antagonizing the phosphorylation of TYK2 and STAT2 (7); however, the viral protein responsible for the IFN inhibitory effect was not identified. Another study implicated HTLV-1 Tax as an inhibitor of IFN signaling via competition of Tax with STAT2 for the coactivators CBP/p300 (53). Taken together, it appears that HTLV-1, and possibly Tax, inhibits IFN signaling.…”