Immunogenetics of the proteasome ubiquitin system

蛋白酶体泛素系统的免疫遗传学

• 批准号: 11470084
• 负责人: KASAHARA Masanori
• 金额: $ 7.94万
• 依托单位: The Graduate University for Advanced Studies
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470084/
• 关键词: MHC; proteasome; chromosomal duplication; IFN-γ; proteasome activator; gene knock-out; 抗原提示; ノックアウトマウス

The proteasome is the multi-subunit protease responsible for the production of peptides bound by MHC class I molecules. In this study, we attempted to gain insights into the structure, function, and origin of IFN-γ regulated proteasome subunits. The results we obtained are as follows :1) Origin of IFN-γ-inducible 20S proteasome subunits : Proposal of the chromosomal duplication model of the MHCThe three IFN-γ-inducible 20S proteasome subunits are thought to have emerged by gene duplication from their constitutively expressed counterparts. We showed that these subunit genes emerged by two rounds of block duplication involving the MHC region thought to have taken place early in vertebrate evolution, most likely in a common ancestor of jawed vertebrates. This series of work has led to the proposal of the chromosomal duplication model of the MHC.2) Structural and functional analysis of the IFN-γ-regulated proteasome subunit genesWe cloned the following IFN-γ-regulated proteasome subunit genes from 129/SvJ mice : Psmb10, Psmb7, Psmb5, Psme1, Psme2, and Psme3, and produced Psme1/Psme2 double knock-out mice as well as mice deficient in the Psme3 gene. Analysis of these mice demonstrated that PA28α/β encoded by Psme1/Psme2 is essential for processing of certain antigens, whereas PA28γ encoded by Psme3 is unlikely to be involved in antigen presentation by MHC class I molecules.

蛋白酶体是一种多亚基蛋白酶，负责产生与MHC I类分子结合的肽。在这项研究中，我们试图深入了解IFN-γ调节的蛋白酶体亚基的结构，功能和起源。1）IFN-γ诱导的20 S蛋白酶体亚基的起源：MHC染色体复制模型的提出三个IFN-γ诱导的20 S蛋白酶体亚基被认为是由组成型表达的20 S蛋白酶体亚基通过基因复制而产生的。我们发现，这些亚基基因出现了两轮块复制涉及MHC区域认为已经发生在脊椎动物进化的早期，最有可能在一个共同的祖先有颚脊椎动物。2）IFN-γ调节的蛋白酶体亚单位基因的结构和功能分析我们从129/SvJ小鼠中克隆了以下IFN-γ调节的蛋白酶体亚单位基因：Psmb 10、Psmb 7、Psmb 5、Psme 1、Psme 2和Psme 3，并产生Psme 1/Psme 2双敲除小鼠以及Psme 3基因缺陷小鼠。对这些小鼠的分析表明，由Psme 1/Psme 2编码的PA 28 α/β对于某些抗原的加工是必需的，而由Psme 3编码的PA 28 γ不太可能参与MHC I类分子的抗原呈递。

项目成果

笠原正典:(分担執筆): "主要組織適合遺伝子複合体,ほか15項目.伊藤正男, 井村裕夫, 高久史麿編:医学大辞典"医学書院,東京(印刷中). (2002)

Masanori Kasahara：（特约作者）：“主要组织相容性复合物，以及其他 15 项。Masao Ito、Hiroo Imura 和 Fumimaro Takahisa：医学词典”Igaku Shoin，东京（2002 年出版）。

Kasahara, M.: "The chromosomal duplication model of the major histocomoatibilitv comolex"Immunol. Rev.. 167. 17-32 (1999)

Kasahara, M.：“主要组织适应性 comolex 的染色体复制模型”免疫。

笠原正典:(分担執筆): "MHCクラスI分子.南山堂医学大事典 改訂19版"南山堂,東京(印刷中). (2002)

Masanori Kasahara：（贡献者）：“MHC I 类分子。Nanzando 医学词典，第 19 版”Nanzando，东京（2002 年出版）。

Kasahara,M.: "Genome paralogy : A new perspective on the organization and origin of the major histocompatibility complex."Curr.Top.Microbiol.Immunol.. 248. 53-66 (2000)

Kasahara, M.：“基因组平行学：主要组织相容性复合体的组织和起源的新视角。”Curr.Top.Microbiol.Immunol.. 248. 53-66 (2000)

Kasahara M.(ed.): "Major Histocompatibility Complex: Evolution, Structure, and Function"Springer-Verlag, Tokyo-Berlin-Heidelberg-New York. 561 (2000)

Kasahara M.（主编）：“主要组织相容性复合物：进化、结构和功能”Springer-Verlag，东京-柏林-海德堡-纽约。