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 adult T cell leukemia (ATL), an aggressive and fatal leukemia of CD4(+) T lymphocytes, and is also associated with a neurological demyelinating disease, tropical spastic paraparesis. The oncogenic potential of HTLV-1 resides in 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 produced in HTLV-1-infected cells. IRF-4 is transiently expressed in anti-CD3 and PMA/ionomycin-stimulated T lymphocytes but not in continuous non-Tax-expressing 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 indirect 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, suggesting a role for IRF-4 in T cell transformation. In an effort to further characterize IRF-4 function, we identified a novel interaction between IRF-4 and FKBP52, a 59-kDa member of the immunophilin family with peptidyl-prolyl isomerase activity (PPIase). IRF-4-FKBP52 association inhibited the interaction between IRF-4 and its DNA-binding partner PU.1, as well as the trans-activation function of IRF-4/PU.1. FKBP52 association resulted in a structural modification of IRF-4, detectable by immunoblot analysis and by IRF-4 partial proteolysis. These results demonstrate a novel posttranslational mechanism of transcriptional control, mediated through the interaction of an immunophilin with a transcriptional regulator.
Sharma
S
S
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, and Department of Microbiology and Immunology, McGill University, Montreal, Canada H3T 1E2.
Mamane
Y
Y
Grandvaux
N
N
Bartlett
J
J
Petropoulos
L
L
Lin
R
R
Hiscott
J
J
D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D015367:Human T-lymphotropic virus 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors; D008213:Lymphocyte Activation; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
D004247:DNA; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D022021:Tacrolimus Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4; C403485:tacrolimus binding protein 4