title: HTLV-1 HBZ protein deregulates interactions between cellular factors and the KIX domain of p300/CBP.
abstract: The complex retrovirus human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia. Deregulation of cellular transcription is thought to be an important step for T-cell transformation caused by viral infection. HTLV-1 basic leucine zipper factor (HBZ) is one of the viral proteins believed to be involved in this process, as it deregulates the expression of numerous cellular genes. In the context of the provirus, HBZ represses HTLV-1 transcription, in part, by binding to the homologous cellular coactivators p300 and CBP. These coactivators play a central role in transcriptional regulation. In this study, we determined that HBZ binds with high affinity to the KIX domain of p300/CBP. This domain contains two binding surfaces that are differentially targeted by multiple cellular factors. We show that two φXXφφ motifs in the activation domain of HBZ mediate binding to a single surface of the KIX domain, the mixed-lineage leukemia (MLL) binding surface. Formation of this interaction inhibits binding of MLL to the KIX domain while enhancing the binding of the transcription factor c-Myb to the opposite surface of KIX. Consequently, HBZ inhibits transcriptional activation mediated by MLL and enhances activation mediated by c-Myb. CREB, which binds the same surface of KIX as c-Myb, also exhibited an increase in activity through HBZ. These results indicate that HBZ is able to alter gene expression by competing with transcription factors for the occupancy of one surface of KIX while enhancing the binding of factors to the other surface.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 278374, USA.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Cook
authors.forename: Nicholas
authors.initials: N
authors.lastname: Polakowski
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lemasson
mesh_terms: D000595:Amino Acid Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000737:chemistry*; D001665:Binding Sites; D015967:Gene Expression Regulation, Viral; D058605:Host-Derived Cellular Factors / Q000737:chemistry*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry; D012191:Retroviridae Proteins; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000737:chemistry*; D050880:p300-CBP Transcription Factors / Q000737:chemistry*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C479751:HBZ protein, human T-cell leukemia virus type I; D058605:Host-Derived Cellular Factors; D020598:Proto-Oncogene Proteins c-myb; D012191:Retroviridae Proteins; D014764:Viral Proteins; D050880:p300-CBP Transcription Factors