HIV-MEDIATED REPRESSION OF MHC CLASS I GENE EXPRESSION

HIV 介导的 MHC I 类基因表达抑制

• 批准号: 5201053
• 负责人: D SINGER
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5201053
• 关键词: MHC class I antigen; gene induction /repression; genetic enhancer element; genetic mapping; genetic promoter element; histocompatibility gene; human immunodeficiency virus 1; protein structure; virus genetics; virus protein

MHC Class I molecules are the major receptors for viral peptides and serve as targets for specific cytotoxic T lymphocytes. HIV-1 specifically decreased activity of an MHC class I gene promoter by up to 12-fold. Repression is mediated by the HIV-1 Tat protein derived from a spliced viral transcript (two-exon Tat), identifying a novel activity for two-exon Tat, distinct from the transactivation of the HIV LTR common to both one-exon and two-exon Tat. Tat represses class I transcription through a direct interaction with the class I promoter. Tat repression can be modulated by strong, upstream enhancer elements. Mapping of functional domains of the Tat protein demonstrates that repression and activation are mediated by distinct and separable domains. Fine mapping of the second exon has localized a segment between amino acids 80 and 86 as essential for repression. Furthermore, a glutamine-rich domain, between 57 and 67 also seems to participate in mediating repression. Elimination of the cysteine- rich domain which is necessary for transactivation does not abrogate repression. However, a central residue shown to be necessary for the interaction of Tat with TBP is necessary for both transactivation and repression.

MHC I类分子是病毒肽的主要受体， 作为特异性细胞毒性T淋巴细胞的靶点。 HIV-1 特异性降低MHC I类基因启动子的活性， 12倍。 抑制是由HIV-1达特蛋白衍生的 从剪接的病毒转录本（两个外显子达特），鉴定一种新的 两个外显子达特的反式激活不同， HIV LTR常见于单外显子和双外显子达特。 达特抑制类 I通过与I类的直接交互进行转录 启动子 达特阻遏可以通过强的上游调控 增强子元件。 对达特蛋白功能结构域的作图表明， 抑制和激活是由不同的和可分离的 域. 第二个外显子的精细定位显示 在氨基酸80和86之间是阻遏所必需的。 此外，谷氨酰胺丰富的结构域，57和67之间似乎也 参与调解镇压。 去除半胱氨酸- 反式激活所必需的丰富的结构域不废除 镇压然而，中心残基被证明是必要的， 达特与TBP相互作用对于反式激活和 镇压