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.Human T-cell leukemia virus type 1 (HTLV-1) is a human retrovirus that is associated with two distinct diseases: adult T-cell leukemia (ATL), an abnormal proliferation of infected CD4 ϩ T lymphocytes, and HTLV-1-associated myelopathy and/or tropical spastic paraparesis, a neurodegenerative disorder (19,48,49). The molecular mechanisms leading to the development of both diseases are unclear, although the viral protein Tax is postulated to play an important role in these processes. Tax functions as a transcription factor and is essential for strong HTLV-1 transcription. Tax activates transcription through three 21-bp repeats that contain imperfect cyclic AMP responsive elements (called viral CREs) situated within the long terminal repeat of the HTLV-1 genome (1,6,14,15,22,27). Tax does not bind DNA alone but interacts with cellular transcription factors from the ATF/CREB family to form complexes that associate with the DNA. Within these complexes, Tax contacts the GC-rich sequences flanking the CRE core (31,37,38,41). The formation of Tax/CREB/DNA complexes is critical for the recruitment of the cellular coactivators CBP/p300 and subsequent high transcriptional activation of the virus (18,21,32,39,58).A number of cellular factors containing basic leucine zipper (bZIP) motifs have been shown to bind the viral CREs in HTLV-1-infected T cells. These factors included the ATF/ CREB family members (ATF-1, ATF-2, CREB, CREB-2, and CRE...

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes

“…HBZ is a potent suppressor of Tax-mediated virus-gene transcription by interacting with activating transcription factor/cAMP responsive element-binding protein (CREB) and CREB-binding protien/p300 on the 5Ј-LTR promoter. 24,34,35 The HBZ role in the tightly regulated pattern of HTLV-1-gene expression also is suggested by HBZ repression of Gag-p19 synthesis in stable virus-producing cell clones. 36 Kinetic study of gene expressions in cells transiently transfected with the HTLV-1-provirus plasmid and in newly infected PBMCs showed that Gag/Pol, Tax/Rex, and Env mRNA are detected first and at their highest levels, whereas HBZ transcription was significantly lower and peaked later.…”

Leucémies T induites par HTLV-1

“…Cette famille comprend des facteurs de transcription capables de s'homodimériser ou de s'hétérodimériser via leur domaine ZIP. Alors que HBZ est incapable de s'homodimériser, il peut former in vivo des dimères avec des membres de la famille ATF/CREB et Jun (Figure 2) [9,[17][18][19][20][21]. En outre, grâce à son domaine d'activation, HBZ interagit aussi avec les cofacteurs transcriptionnels CBP/p300 [22].…”

“…Il est frappant de constater que HBZ cible les facteurs nucléaires qui sont impliqués dans le contrôle de la transcription virale Tax-dépendante (Figure 1). En fait, nous avons pu démontrer que HBZ régule négativement la transcription des autres gènes viraux en inhibant l'association de Tax avec CREB sur le promoteur du LTR 5' et en empêchant le recrutement de CBP/p300 sur ce même promoteur (Figure 3) [21,22]. …”

HTLV-1 Tax Effects on Cellular Mitotic Regulation

“…In HTLV-1 infected cells, Tax expression is negatively regulated by Rex, p30, and a newly discovered HTLV-1 basic leucine zipper (HBZ) factor encoded by an anti-sense mRNA transcribed from the 3' end of the proviral DNA (5,18,103,168). Despite the role of Tax in cell transformation and leukemogenesis, the leukemic cells of approximately 60% of ATL patients do not express tax transcript.…”