Activation and regulation of interferon regulatory factor 4 in HTLV type 1-infected T lymphocytes

The human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a dult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4(+) T ly mphocytes, and is also associated with a neurological demyelinating disease , tropical spastic paraparesis. The oncogenic potential of HTLV-1 resides i n the 353-aa, 40-kDa viral Tax: oncoprotein, a positive regulator of viral gene transcription. A novel member of the interferon regulatory factor (IRF ) family of transcription factors, IRF-4, was shown to be constitutively pr oduced in HTLV-infected cells. IRF-4 is transiently expressed in anti-CD3 a nd PMA/ionomycin-stimulated T lymphocytes but not in continuous non-Tax-exp ressing T cell lines. In transient coexpression assays, HTLV-1 Tax protein induced the 1.2-kb IRF-4 promoter, indicating that Tax functions as an indi rect trans-activator of the IRF-4 gene. Furthermore, IRF-4 levels in HTLV-1 -infected cells appear to be proportional to the level of Tax expression, s uggesting a role for IRF-4 in T cell transformation. In an effort to furthe r characterize IRF-4 function, we identified a novel interaction between IR F-4 and FKBP52, a 59-kDa member of the immunophilin family with peptidyl-pr olyl isomerase activity (PPIase), IRF-4-FKBP52 association inhibited the in teraction between IRF-4 and its DNA-binding partner IPU.1, as well as the t rans-activation function of IRE-4/PU.1. FKBP52 association resulted in a st ructural modification of IRF-4, detectable by immunoblot analysis and by IR F-4 partial proteolysis. These results demonstrate a novel posttranslationa l mechanism of transcriptional control, mediated through the interaction of an immunophilin with a transcriptional regulator.