title: Human T-cell leukemia virus type 1 (HTLV-1) bZIP protein interacts with the cellular transcription factor CREB to inhibit HTLV-1 transcription.
abstract: The complex human T-cell leukemia virus type 1 (HTLV-1) retrovirus encodes several proteins that are unique to the virus within its 3'-end region. Among them, the viral transactivator Tax and posttranscriptional regulator Rex are well characterized, and both positively regulate HTLV-1 viral expression. Less is known about the other regulatory proteins encoded in this region of the provirus, including the recently discovered HBZ protein. HBZ has been shown to negatively regulate basal and Tax-dependent HTLV-1 transcription through its ability to interact with specific basic-leucine zipper (bZIP) proteins. In the present study, we found that HBZ reduces HTLV-1 transcription and virion production. We then characterized the interaction between HBZ and the cellular transcription factor CREB. CREB plays a critical role in Tax-mediated HTLV-1 transcription by forming a complex with Tax that binds to viral cyclic AMP-response elements (CREs) located within the viral promoter. We found that HBZ and CREB interact in vivo and directly in vitro, and this interaction occurs through the bZIP domain of each protein. We also found that CREM-Ia and ATF-1, which share significant homology in their bZIP domains with the bZIP domain of CREB, interact with HBZ-bZIP. The interaction between CREB and HBZ prevents CREB binding to the viral CRE elements in vitro and in vivo, suggesting that the reduction in HTLV-1 transcription by HBZ is partly due to the loss of CREB at the promoter. We also found that HBZ displaces CREB from a cellular CRE, suggesting that HBZ may deregulate CREB-dependent cellular gene expression.
authors.affiliation: East Carolina University, Department of Microbiology and Immunology, Brody School of Medicine, 600 Moye Blvd., Greenville, NC 27834, USA. lemassoni@ecu.edu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lemasson
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lewis
authors.forename: Nicholas
authors.initials: N
authors.lastname: Polakowski
authors.forename: Patrick
authors.initials: P
authors.lastname: Hivin
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Cavanagh
authors.forename: Sabine
authors.initials: S
authors.lastname: Thébault
authors.forename: Benoit
authors.initials: B
authors.lastname: Barbeau
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Nyborg
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Mesnard
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D017362:Cyclic AMP Response Element-Binding Protein; D016356:Gene Products, tax; D014764:Viral Proteins