title: Human T-cell leukemia virus type 3 (HTLV-3) and HTLV-4 antisense-transcript-encoded proteins interact and transactivate Jun family-dependent transcription via their atypical bZIP motif.
abstract: Human T-cell leukemia virus types 3 and 4 (HTLV-3 and HTLV-4) are recently isolated retroviruses. We have previously characterized HTLV-3- and HTLV-4-encoded antisense genes, termed APH-3 and APH-4, respectively, which, in contrast to HBZ, the HTLV-1 homologue, do not contain a typical bZIP domain (M. Larocque É Halin, S. Landry, S. J. Marriott, W. M. Switzer, and B. Barbeau, J. Virol. 85:12673-12685, 2011, doi:10.1128/JVI.05296-11). As HBZ differentially modulates the transactivation potential of various Jun family members, the effect of APH-3 and APH-4 on JunD-, c-Jun-, and JunB-mediated transcriptional activation was investigated. We first showed that APH-3 and APH-4 upregulated the transactivation potential of all tested Jun family members. Using an human telomerase catalytic subunit (hTERT) promoter construct, our results also highlighted that, unlike HBZ, which solely modulates hTERT expression via JunD, both APH-3 and APH-4 acted positively on the transactivation of the hTERT promoter mediated by tested Jun factors. Coimmunoprecipitation experiments demonstrated that these Jun proteins interacted with APH-3 and APH-4. Although no activation domain was identified for APH proteins, the activation domain of c-Jun was very important in the observed upregulation of its activation potential. We further showed that APH-3 and APH-4 required their putative bZIP-like domains and corresponding leucine residues for interaction and modulation of the transactivation potential of Jun factors. Our results demonstrate that HTLV-encoded antisense proteins behave differently, and that the bZIP-like domains of both APH-3 and APH-4 have retained their interaction potential for Jun members. These studies are important in assessing the differences between HBZ and other antisense proteins, which might further contribute to determining the role of HBZ in HTLV-1-associated diseases. IMPORTANCE HBZ, the antisense transcript-encoded protein from HTLV-1, is now well recognized as a potential factor for adult T-cell leukemia/lymphoma development. In order to better appreciate the mechanism of action of HBZ, comparison to antisense proteins from other HTLV viruses is important. Little is known in relation to the seemingly nonpathogenic HTLV-3 and HTLV-4 viruses, and studies of their antisense proteins are limited to our previously reported study (M. Larocque É Halin, S. Landry, S. J. Marriott, W. M. Switzer, and B. Barbeau, J. Virol. 85:12673-12685, 2011, doi:10.1128/JVI.05296-11). Here, we demonstrate that Jun transcription factors are differently affected by APH-3 and APH-4 compared to HBZ. These intriguing findings suggest that these proteins act differently on viral replication but also on cellular gene expression, and that highlighting their differences of action might lead to important information allowing us to understand the link between HTLV-1 HBZ and ATL in infected individuals.
authors.affiliation: Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Québec, Canada Centre de Recherche BioMed, Université du Québec à Montréal, Montréal, Québec, Canada Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Émilie
authors.initials: É
authors.lastname: Larocque
authors.affiliation: Université Montpellier 1, CNRS, UM5236, CPBS, Montpellier, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: André-Arpin
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, Unité Mixte de Recherche 5239, Centre National de la Recherche Scientifique, Ecole Normale Supérieure, UMS3444 BioSciences Lyon-Gerland, Lyon, France.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Borowiak
authors.affiliation: Département de Microbiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Lemay
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Switzer
authors.affiliation: Laboratoire de Biologie Moléculaire de la Cellule, Unité Mixte de Recherche 5239, Centre National de la Recherche Scientifique, Ecole Normale Supérieure, UMS3444 BioSciences Lyon-Gerland, Lyon, France.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Duc Dodon
authors.affiliation: Université Montpellier 1, CNRS, UM5236, CPBS, Montpellier, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Mesnard
authors.affiliation: Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, Québec, Canada Centre de Recherche BioMed, Université du Québec à Montréal, Montréal, Québec, Canada barbeau.benoit@uqam.ca.
authors.forename: Benoit
authors.initials: B
authors.lastname: Barbeau
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D016373:DNA, Antisense / Q000235:genetics*; D017977:Deltaretrovirus / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D056187:Human T-lymphotropic virus 3 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D016373:DNA, Antisense; D016755:Proto-Oncogene Proteins c-jun; D014764:Viral Proteins; D019098:Telomerase