title: Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12(I).
abstract: Human T-lymphotropic virus type 1 (HTLV-1) is the agent of an aggressive malignancy of CD4(+) T lymphocytes, called adult T-cell lymphoma/leukemia, and is associated with numerous immune-mediated diseases. To establish infection, HTLV-1 must activate targeted T cells during early stages of infection. We recently demonstrated that the HTLV-1 accessory protein p12(I) is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12(I) in lymphocyte activation. To test whether p12(I) modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NF-kappaB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12(I)-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12(I) specifically induced NFAT-mediated transcription approximately 20-fold in synergy with the Ras/mitogen-activated protein kinase pathway, but did not influence AP-1- or NF-kappaB-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N'-1,2-ethanediylbis(oxy-2,1-phenylene)-bis-N-2-(acetyloxy)methoxy-2-oxoethyl]-[bis(acetyloxy)methyl ester], and a dominant negative mutant of NFAT2 abolished the p12(I)-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-gamma and LAT (linker for activation of T cells) did not affect p12(I)-induced NFAT activity. Importantly, p12(I) functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12(I) in calcium-dependent activation of NFAT-mediated transcription in lymphoid cells. We propose a novel mechanism by which HTLV-1, a virus associated with lymphoproliferative disease, dysregulates common T-cell activation pathways critical for the virus to establish persistent infection.
authors.affiliation: Center for Retrovirus Research and Department of Veterinary Biosciences, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Björn
authors.initials: B
authors.lastname: Albrecht
authors.forename: Celine D
authors.initials: CD
authors.lastname: D'Souza
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: K Mark
authors.initials: KM
authors.lastname: Coggeshall
authors.forename: Michael D
authors.initials: MD
authors.lastname: Lairmore
mesh_terms: D002118:Calcium; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017930:Genes, Reporter; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C084305:p12I protein, Human T-lymphotropic virus 1; D002118:Calcium