Immunogenetics of the proteasome ubiquitin system

蛋白酶体是一种多亚基蛋白酶，负责产生由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。研究结果如下：1)IFN-γ诱导的20S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20S蛋白酶体亚基被认为是通过基因复制从其组成表达的对偶体中产生的。我们发现，这些亚基基因是通过涉及MHC区域的两轮块重复出现的，这种重复被认为发生在脊椎动物进化的早期，最有可能发生在有颌脊椎动物的共同祖先身上。本研究从129/SvJ小鼠中克隆了IFN-γ调控的蛋白酶体亚基基因：Psmb10、Psmb7、Psmb5、Psme1、Psme2和Psme3，获得了Psme1/Psme2双敲除小鼠和Psme3基因缺失小鼠。对这些小鼠的分析表明，由Psme1/Psme2编码的PA28α/β对某些抗原的加工至关重要，而由Psme3编码的PA28γ不太可能参与MHC I类分子的抗原呈递。

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.