An interaction between the human T cell leukemia virus type 1 basic leucine zipper factor (HBZ) and the KIX domain of p300/CBP contributes to the down-regulation of tax-dependent viral transcription by HBZ.
Activation of human T cell leukemia virus type 1 (HTLV-1) transcription is established through the formation of protein complexes on the viral promoter that are essentially composed of the cellular basic leucine zipper (bZIP) transcription factor cAMP-response element-binding protein (CREB (or certain other members of the ATF/CREB family), the HTLV-1-encoded transactivator Tax, and the pleiotropic cellular coactivators p300/CBP. HTLV-1 bZIP factor (HBZ) is a protein encoded by HTLV-1 that contains a bZIP domain and functions to repress HTLV-1 transcription. HBZ has been shown to repress viral transcription by dimerizing with CREB, which occurs specifically through the bZIP domain in each protein, and preventing CREB from binding to the DNA. However, we previously found that HBZ causes only partial removal of CREB from a chromosomally integrated viral promoter, and more importantly, an HBZ mutant lacking the COOH-terminal bZIP domain retains the ability to repress viral transcription. These results suggest that an additional mechanism contributes to HBZ-mediated repression of HTLV-1 transcription. In this study, we show that HBZ binds directly to the p300 and CBP coactivators. Two LXXLL-like motifs located within the NH(2)-terminal region of HBZ are important for this interaction and specifically mediate binding to the KIX domain of p300/CBP. We provide evidence that this interaction interferes with the ability of Tax to bind p300/CBP and thereby inhibits the association of the coactivators with the viral promoter. Our findings demonstrate that HBZ utilizes a bipartite mechanism to repress viral transcription.
Clerc
Isabelle
I
Université Montpellier 1 and CNRS, UM5236, Centre d'Etudes d'Agents Pathogènes et Biotechnologies pour la Santé (CPBS), Montpellier, France.
Polakowski
Nicholas
N
André-Arpin
Charlotte
C
Cook
Pamela
P
Barbeau
Benoit
B
Mesnard
Jean-Michel
JM
Lemasson
Isabelle
I
D020816:Amino Acid Motifs / Q000502:physiology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D015536:Down-Regulation / Q000502:physiology*; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D012191:Retroviridae Proteins; D014158:Transcription, Genetic / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*
D050976:Basic-Leucine Zipper Transcription Factors; D016356:Gene Products, tax; C479751:HBZ protein, human T-cell leukemia virus type I; D012191:Retroviridae Proteins; D014764:Viral Proteins; C514970:tax protein, Human T-lymphotrophic virus 1; D050880:p300-CBP Transcription Factors