title: Human T lymphotropic virus type 1 accessory protein p12I modulates calcium-mediated cellular gene expression and enhances p300 expression in T lymphocytes.
abstract: Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T cell leukemia/lymphoma (ATLL), an aggressive CD4+ T lymphocyte malignancy. Activation of T lymphocytes is required for effective retroviral integration into the host cell genome and subsequent viral replication, but the molecular mechanisms involved in HTLV-1-mediated T cell activation remain unclear. HTLV-1 encodes various accessory proteins such as p12I, which has been demonstrated to be critical for HTLV-1 infectivity in vivo in rabbits and in vitro in quiescent primary human T lymphocytes. This hydrophobic protein localizes in the endoplasmic reticulum, increases intracellular calcium, and activates nuclear factor of activated T cell-mediated transcription. To further elucidate the role of p12I in regulation of cellular gene expression, we performed gene array analysis on stable p12I-expressing Jurkat T cells, using Affymetrix U133A arrays. Our data indicate that p12I altered the expression of genes associated with a network of interrelated pathways including T cell signaling, cell proliferation, and apoptosis. Expression of several calcium-regulated genes was found to be altered by p12I, consistent with known properties of the viral protein. Gene array findings were confirmed by semiquantitative RT-PCR in Jurkat T cells and primary CD4+ T lymphocytes. Furthermore, dose-dependent expression of p12I in Jurkat T cells resulted in significant increases in p300 and p300-dependent transcription. This is the first report of a viral protein influencing the transcription of p300, a rate-limiting coadapter critical in HTLV-1-mediated T cell activation. Collectively, our data strongly indicate that HTLV-1 p12I modulates cellular gene expression patterns to hasten the activation of T lymphocytes and thereby promote efficient viral infection.
authors.affiliation: Center for Retrovirus Research and Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Amrithraj
authors.initials: A
authors.lastname: Nair
authors.forename: Bindhu
authors.initials: B
authors.lastname: Michael
authors.forename: Hajime
authors.initials: H
authors.lastname: Hiraragi
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: Gerold
authors.initials: G
authors.lastname: Feuer
authors.forename: Kathleen
authors.initials: K
authors.lastname: Boris-Lawrie
authors.forename: Michael
authors.initials: M
authors.lastname: Lairmore
mesh_terms: D017209:Apoptosis; D002455:Cell Division; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D009687:Nuclear Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C084305:p12I protein, Human T-lymphotropic virus 1