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RESEARCH FOR THE MHC CLASS I RESTRICTED ANTIGEN PROCESSING AND PRESENTATION

MHC I 类限制性抗原加工和表达的研究

基本信息

批准号：
06671592
负责人：
AKIYAMA Kinya
金额：
$ 1.34万
依托单位：
THE UNIVERSITY OF TOKUSHIMA
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

The proteasome is a unusually large multifunctional protease complex consisting of multiple polypeptides, which catalyzes non-lysosomal, ATP-dependent selective breakdown of ubiquitinated proteins and is thought to be a putative processing enzyme responsible for major histocompatibility complex (MHC) class I-restricted antigen presentation. Recently, we reported that a major immunomodulatory cytokine, gamma interferon (gamma-IFN), induced not only marked synthesis of the MHC-encoded proteasome subunits LMP2 and LMP7, but also almost complete loss of two unidentified proteasome subunits tentatively designated as X and Y in various human cells, which alters the proteolytic specificity of proteasomes perhaps more appropriate for the immunological processing of endogenous antigens. Based on partial amino acid sequence analysis of X and Y,we suggested that subunit X is a proteasomal subunit similar to LMP7, and that subunit Y is identical to the LMP2-related proteasomal subunit delta. Final … More ly, molecular cloning of cDNAs encoding X and Y showed that these X and Y are a novel class of proteasomal subunits with high homology to LMP7 and LMP2, respectively. Moreover, recently we found two novel proteasome subunits expressed reciprocally in response to interferon-gamma. Molecular cloning of a cDNA encoding one subunit designated as Z down-regulated by interferon-gamma showed that it is a novel proteasomal subunit with high homology to MECL1, which is markedly induced by interferon-gamma (Submitted for publication). Thus, interferon-gamma may induce subunit replacements of not only X and Y by LMP7 and LMP2, respectively, but also of Z by MECL1, producing proteasomes responsible for major histocompatibility complex (MHC) class I-restricted antigen presentation.The primary structures of two proteins that comprise PA28, an activator of the 20S proteasome, have been determined by cDNA cloning and sequencing. These protein subunits, termed PA28a and PA28b, are about 50% identical to one another and are highly conserved between rat and human. Less

蛋白酶体是由多个多肽组成的异常大的多功能蛋白酶复合物，其催化泛素化蛋白的非溶酶体、ATP依赖性选择性分解，并且被认为是负责主要组织相容性复合物（MHC）I类限制性抗原呈递的推定加工酶。最近，我们报道了一种主要的免疫调节细胞因子，γ干扰素（γ-IFN），诱导不仅显着的MHC编码的蛋白酶体亚基LMP 2和LMP 7的合成，但也几乎完全丧失了两个未知的蛋白酶体亚基暂定为X和Y在各种人类细胞中，这改变了蛋白酶体的蛋白水解特异性，可能更适合于内源性抗原的免疫处理。基于X和Y的部分氨基酸序列分析，我们认为X亚基是与LMP 7相似的蛋白酶体亚基，Y亚基与LMP 2相关的蛋白酶体亚基δ相同。最终 ...更多信息对编码X和Y的cDNA进行分子克隆，结果表明X和Y分别是一类新的蛋白酶体亚基，与LMP 7和LMP 2具有高度同源性。此外，最近我们发现两个新的蛋白酶体亚基表达的干扰素γ。编码一个被干扰素-γ下调的称为Z的亚基的cDNA的分子克隆表明，它是一种新的蛋白酶体亚基，与MECL 1具有高度同源性，MECL 1被干扰素-γ显著诱导（提交出版）。因此，干扰素-γ不仅可以诱导LMP 7和LMP 2分别取代X和Y亚基，而且还可以诱导MECL 1取代Z亚基，产生负责主要组织相容性复合体（MHC）I类限制性抗原呈递的蛋白酶体。这些蛋白质亚基，称为PA 28 a和PA 28 b，彼此约50%相同，并且在大鼠和人类之间高度保守。少