Regulation of HTLV-1 and cellular gene transcription by the viral protein HBZ

病毒蛋白 HBZ 对 HTLV-1 和细胞基因转录的调节

• 批准号: 7887334
• 负责人: Isabelle Michele Lemasson
• 金额: $ 26.63万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887334
• 关键词: Acetyltransferase; Address; Adult; Affect; Affinity; Binding; Binding Sites; Biological; Biology; Blood; Breast Feeding; CREB1 gene; Cell Nucleus; Child; Clinical; Coitus; Collection; Complex; Consensus; DNA Binding; Data; Development; Diagnosis; Dimerization; Disease; E1A-associated p300 protein; EP300 gene; Family; Gene Expression; Gene Expression Microarray Analysis; Genes; Genetic Transcription; Goals; Human T-lymphotropic virus 1; In Vitro; Infection; JUN gene; Leucine Zippers; Life; Malignant Neoplasms; Mediating; Mothers; N-terminal; Neurodegenerative Disorders; Oncogene Deregulation; Play; Process; Proteins; Proviruses; Regulation; Relative (related person); Repression; Research; Retroviridae; Role; T-Cell Leukemia; T-Cell Proliferation; T-Lymphocyte; Testing; Transcription Factor AP-1; Transcription Regulatory Protein; Viral; Viral Proteins; Virus; Virus Latency; activating transcription factor 1; activating transcription factor 4; bZIP Domain; base; dimer; gene repression; in vivo; insight; leukemia; member; prevent; promoter; public health relevance; transcription factor; transmission process

DESCRIPTION (provided by applicant): Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that is the causative agent of a variety of clinical disorders including adult T-cell leukemia (ATL), an aggressive and often fatal malignancy of mature activated T-cells. ATL is frequently diagnosed after several decades of infection, suggesting that a long period of viral latency contributes to the development of this disease. The HTLV-1 basic leucine zipper factor (HBZ) is believed to play a role in viral latency and T-cell proliferation. This protein is localized in the nucleus and carries a basic leucine zipper (bZIP) domain that promotes protein dimerization through interactions with appropriate leucine zippers in other proteins. Cellular bZIP factors that are bound by HBZ include certain AP-1 transcription factor components (c-Jun, JunB, JunD) and members of the ATF/CREB family (ATF-1, CREB, CREM and CREB-2). Overall, interactions with HBZ are believed to repress transcription by preventing factors from binding the DNA, an effect that is correlated with the atypical basic region in the HBZ bZIP domain. We found that HBZ also binds directly to the cellular coactivators p300 and CBP, which is mediated through regions of the viral protein outside its bZIP domain. In the context of the HTLV-1 promoter, we found that binding of HBZ to both CREB and p300/CBP is essential to achieve full repression of transcription. As the HBZ gene is uniquely encoded on the minus strand at the 3' end of the provirus, its expression is not affected by this and other mechanisms of repression targeting the 5' LTR (the normal viral promoter). It is likely that the binding of HBZ to cellular bZIP factors and p300/CBP underlie its ability to deregulate expression of many cellular genes. To gain insight into the mechanisms by which HBZ affects transcription, we have evaluated its interactions with cellular transcriptional regulators and we have identified genes that it targets. We have obtained evidence that complexes formed between HBZ and ATF/CREB factors are structurally distinct from complexes formed with AP-1 factors. In addition, we found that HBZ directly targets multiple domains of p300/CBP, including the KIX, ZZ and TAZ2 domains. In this proposal we will address the functional consequences of these interactions. In Aim 1, we propose to dissect the interaction between HBZ and p300/CBP, and determine downstream effects of this interaction, including alterations in the abilities of the coactivator to interact with and/or acetylate specific cellular proteins. In Aim 2, we will compare the interaction of HBZ with ATF/CREB and AP-1 proteins. In Aim 3, we will characterize mechanisms of HBZ-mediated deregulation of cellular gene expression. We will test whether abnormal expression of specific genes underlies certain biological aspects of HTLV-1 infection that may relate to development or clinical presentations of ATL. PUBLIC HEALTH RELEVANCE: Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with an aggressive leukemia and a neurodegenerative disease. This virus encodes a viral protein, HTLV-1 bZIP factor (HBZ), which is uniquely encoded on the minus strand of the provirus and is not transcribed from the 5' LTR (the normal viral promoter). This proposal investigates how HBZ is involved in regulating viral and cellular transcription by targeting bZIP transcription factors and key coactivators required for viral and cellular transcription.

描述（由申请人提供）：人类T细胞白血病病毒1型（HTLV-1）是一种复杂的逆转录病毒，是多种临床疾病（包括成人T细胞白血病（ATL））的病毒药物，是一种积极的成熟活性T细胞的侵略性和致命性恶性肿瘤。经过数十年的感染后，经常诊断出ATL，这表明长期的病毒潜伏期有助于这种疾病的发展。 HTLV-1碱性亮氨酸拉链因子（HBZ）被认为在病毒潜伏期和T细胞增殖中起作用。该蛋白质位于细胞核中，并带有基本的亮氨酸拉链（BZIP）结构域，该结构域通过与其他蛋白质中适当的亮氨酸拉链相互作用来促进蛋白质二聚化。由HBZ结合的细胞BZIP因子包括某些AP-1转录因子成分（C-Jun，Junb，Jund）和ATF/CREB家族的成员（ATF-1，CREB，CREB，CREM和CREB-2）。总体而言，据信与HBZ的相互作用通过预防因素结合DNA来抑制转录，这种作用与HBZ BZIP结构域中的非典型基本区域相关。我们发现HBZ还直接与细胞共激活因子p300和CBP结合，该p300和CBP是通过其BZIP结构域外的病毒蛋白区域介导的。在HTLV-1启动子的背景下，我们发现HBz与CREB和P300/CBP的结合对于实现转录的完全抑制至关重要。由于HBz基因在病毒的3'末端的负链上唯一地编码，因此其表达不受针对5'LTR（正常病毒启动子）的抑制和其他抑制机制的影响。 HBz与细胞BZIP因子的结合和p300/CBP的结合是其放大许多细胞基因表达的能力的基础。为了深入了解HBZ影响转录的机制，我们评估了其与细胞转录调节剂的相互作用，并确定了其靶向的基因。我们已经获得了证据表明，HBZ和ATF/CREB因子之间形成的复合物在结构上与AP-1因子形成的复合物不同。此外，我们发现HBZ直接靶向P300/CBP的多个域，包括KIX，ZZ和TAZ2域。在此提案中，我们将解决这些相互作用的功能后果。在AIM 1中，我们建议剖析HBZ和P300/CBP之间的相互作用，并确定这种相互作用的下游效应，包括共激活因子与与特定细胞蛋白相互作用和/或乙酰化特异性细胞蛋白相互作用的能力的改变。在AIM 2中，我们将比较HBz与ATF/CREB和AP-1蛋白的相互作用。在AIM 3中，我们将表征HBZ介导的细胞基因表达放松管制的机制。我们将测试特定基因的异常表达是否是HTLV-1感染的某些生物学方面是与ATL的发育或临床表现有关的。 公共卫生相关性：人类T细胞白血病1型（HTLV-1）是与侵略性白血病和神经退行性疾病相关的逆转录病毒。该病毒编码病毒蛋白HTLV-1 BZIP因子（HBZ），该病毒蛋白是在病毒的负链上唯一编码的，并且未从5'LTR（正常病毒启动子）转录。该提案研究了HBZ如何通过靶向病毒和细胞转录所需的BZIP转录因子以及关键的共激活因子来调节病毒和细胞转录。