Activation of Nuclear Factor of Activated T Cells by Human T-Lymphotropic Virus Type 1 Accessory Protein p12I
AUTOR(ES)
Albrecht, Björn
FONTE
American Society for Microbiology
RESUMO
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 p12I is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12I in lymphocyte activation. To test whether p12I modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NF-κB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12I-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12I 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-κB-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 p12I-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-γ and LAT (linker for activation of T cells) did not affect p12I-induced NFAT activity. Importantly, p12I functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12I 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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=136046Documentos Relacionados
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