Responses of MHC Class I Genes to Exogeneous Stimuli

MHC I 类基因对外源刺激的反应

• 批准号: 8552620
• 负责人: Dinah S. Singer
• 金额: $ 17.94万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8552620
• 关键词: Acetyltransferase; Autoantigens; Autoimmune Diseases; Bare Lymphocyte Syndromes; Binding; Bypass; Cell Surface Receptors; Complex; Critical Pathways; Data; Disease; Employee Strikes; Failure; General Transcription Factors; Genes; Genetic Transcription; Goals; HIV; Hormones; Immune response; Immunologic Surveillance; Infection; Inflammation; Interferon Type II; Interferons; Lead; Link; MHC Class I Genes; MHC Class II Genes; Major Histocompatibility Complex; Maps; Modeling; Molecular; Pathway interactions; Peptides; Phosphotransferases; Play; Protein-Serine-Threonine Kinases; Proteins; Regulation; Regulatory Pathway; Reporting; Research; Role; Signal Pathway; Signal Transduction; Stimulus; TAF7 gene; TATA-Binding Protein Associated Factors; Tissues; Transcription Coactivator; Transcription Initiation; Tumor Antigens; base; carcinogenesis; cytokine; extracellular; human TAF1 protein; neoplastic cell; novel; pathogen; programs; promoter; response; transcription factor; tumor

The TFIID components TAF7 and TAF1 regulate eukaryotic transcription initiation. TAF7 regulates transcription initiation of TAF1-dependent genes by binding to the acetyltransferase (AT) domain of TAF1 and inhibiting the enzymatic activity that is essential for transcription. TAF7 is released from the TAF1/TFIID complex upon completion of preinitiation complex assembly, allowing transcription to initiate. However, not all transcription is TAF1-dependent and the role of TAF7 in regulating TAF1-indepedent transcription has not been defined. The IFN-gamma--induced transcription factor CIITA is a coactivator and general transcription factor that regulates both MHC Class I and Class II gene transcription, and is thus critical to activated immune response. Known as the master regulator of Class II expression, CIITA is required for both Class II transcription and activated Class I expression. Its deficiency is linked to bare lymphocyte syndrome. Comparison of eukaryotic basal class I transcription and interferon-activated transcription initiation reveals similar preinitiation complex recruitment mechanisms, and striking parallels between their respective critical components, the TATA-binding protein (TBP)-associated factor 1 (TAF1) and CIITA. Both TAF1 and CIITA possess instrinsic acetyltransferase (AT) activity required to activate MHC transcription, which is regulated by TAF7. Moreover, CIITA can bypass the requirement for TAF1 to activate both the MHC class I and II promoters. TAF1 has two distinct kinase activities, located with its amino-terminal and carboxy-terminal domains. However, despite the striking functional parallels between CIITA and TAF1, no similar kinase activity has been reported for CIITA thus far. We have now identified the transcriptional coactivator CIITA as a novel atypical serine-threonine kinase whose substrates include various general transcription factors. We have characterized the kinase activity of the protein and mapped the putative kinase domains. We have proposed a model in which the kinase activity of CIITA serves a function similar to that of TAF1, in which it regulates TAF7 binding and release, and thus MHC transcription initiation. This may elucidate a novel role for CIITA in the regulation of activated transcription initiation and stimulated immune response during pathogenic infection.

TFIID组件TAF7和TAF1调节真核转录启动。 TAF7通过与TAF1的乙酰转移酶（AT）结合并抑制转录必不可少的酶促活性来调节TAF1依赖性基因的转录启动。 TAF7在完成前的复合体组装后从TAF1/TFIID复合物中释放出来，从而启动转录。但是，并非所有转录都是taf1依赖性的，并且尚未定义TAF7在调节TAF1内部转录中的作用。 IFN-GAMMA诱导的转录因子CIITA是调节MHC I类和II类基因转录的共激活因子和一般转录因子，因此对于激活的免疫反应至关重要。 CIITA被称为II类表达的主要调节剂，II类转录和激活的I类表达都需要CIITA。它的缺乏与裸露的淋巴细胞综合征有关。真核基础I类转录和干扰素激活的转录起始的比较揭示了相似的预处理复杂募集机制，以及它们各自的关键成分之间的显着性相似之处，即TATA结合蛋白（TBP）与之相关的因子1（TAF1）和CIITA。 TAF1和CIITA都具有激活MHC转录所需的辅助乙酰转移酶（AT）活性，该活性受TAF7调节。此外，CIITA可以绕过TAF1激活MHC I和II类启动子的要求。 TAF1具有两种不同的激酶活性，其氨基末端和羧基末端结构域。然而，尽管CIITA和TAF1之间的功能相似，但到目前为止，CIITA尚无类似的激酶活性。现在，我们已经将转录共激活因子CIITA确定为一种新型非典型丝氨酸 - 硫代激酶，其底物包括各种一般转录因子。我们已经表征了蛋白质的激酶活性，并映射了假定的激酶结构域。 我们提出了一个模型，其中CIITA的激酶活性具有与TAF1相似的函数，在该函数中，它调节TAF7结合和释放，从而调节MHC转录起始。这可以阐明CIITA在调节活化转录起始和致病感染期间刺激免疫反应中的新作用。