Analysis of relationship between autoimmune response and, structure and function of proteasome-PCNA multiprotein complex

自身免疫反应与蛋白酶体-PCNA多蛋白复合物结构和功能关系分析

• 批准号: 16590995
• 负责人: TAKASAKI Yoshinari
• 金额: $ 1.15万
• 依托单位: JUNTENDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590995/
• 关键词: proteasome; PCNA; Ki; autoantibody; autoantigen; プロテアソーム; 自己抗原; 自己抗体

We have previously shown that a group of anti-PCNA monoclonal antibodies (mAbs) raised in our laboratory can react with PCNA bound to or interacting with other proteins associated with cell proliferation (PCNA complexes). In addition, we have found that proteasome is also interacting with PCNA and showed that the proteasome interacting with PCNA is the hybrid-type proteasome consisted of PA700, 20S proteasone and PA28(γ). We then analyzed autoimmune response of proteins in the proretasome in patients with various connective tissue disease, and found that 24% of sera from patients with systemic lupus erythematosus (SLE) and 13% of sera from Sjogren's syndrome (SjS) reacted with PA28γ, whereas 26% of lupus sera and 23% of sera from SjS reacted with PA28α. These results suggested that autoantigens targeted by SLE and SjS are different although both two proteins are the same components of proteasome. We also found that the occurrence of the autoimmune response to these proteins had a significant linkage. To analyze the mechanisms of the linkage, we tested autoimmune response to the components of 20S proteasome that is interacting with both two proteins. Then, we found that the frequency of antibodies to PA28αand PA28γ became three times higher if the sera were reactive with α subunit of 20S proteasome. In addition, a linkage of autoimmune response between PCNA and proteasome was also shown, and the frequency of antibodies to PCNA increased 10 times higher among those sera. Taken together, these findings suggest that "antige presentation" is playing a critical role to induce the autoimmune response to the PCNA complex including proteasome.

我们以前已经表明，在我们的实验室中提出的一组抗PCNA单克隆抗体（mAb）可以与PCNA结合或与其他蛋白质相互作用与细胞增殖（PCNA复合物）。此外，我们还发现蛋白酶体也与PCNA相互作用，并证明与PCNA相互作用的蛋白酶体是由PA700、20S蛋白酶和PA28（γ）组成的混合型蛋白酶体。然后我们分析了各种结缔组织病患者前体蛋白的自身免疫反应，发现24%的系统性红斑狼疮（SLE）患者血清和13%的干燥综合征（SjS）血清与PA 28 γ反应，而26%的狼疮血清和23%的SjS血清与PA 28 α反应。这些结果表明，SLE和SjS的靶向自身抗原是不同的，尽管这两种蛋白质是相同的蛋白酶体组分。我们还发现，这些蛋白的自身免疫反应的发生有显着的联系。为了分析这种联系的机制，我们测试了与两种蛋白质相互作用的20S蛋白酶体组分的自身免疫反应。结果发现，与20S蛋白酶体α亚基反应的血清，其抗PA 28 α和PA 28 γ抗体的频率可提高3倍。此外，PCNA和蛋白酶体之间的自身免疫反应的联系也被证明，和PCNA的抗体的频率增加了10倍以上，这些血清。总之，这些发现表明，“抗原呈递”在诱导对包括蛋白酶体在内的PCNA复合物的自身免疫反应中起着关键作用。

项目成果

Anticyclic citrullinated peptide antibodies in patients with mixed connective tissue disease.

• DOI: 10.1007/s10165-004-0325-2
• 发表时间: 2004-01-01
• 期刊: Modern rheumatology
• 影响因子: 2.2
• 作者: Takasaki, Yoshinari;Yamanaka, Kenjiro;Hashimoto, Hiroshi
• 通讯作者: Hashimoto, Hiroshi

Glyceraldehyde 3-phosphate dehydrogenase is a novel autoantigen leading autoimmune responses to proliferating cell nuclear antigen multiprotein complexes in lupus patients.

• DOI: 10.1093/intimm/dxh131
• 发表时间: 2004-09
• 期刊: International immunology
• 影响因子: 4.4
• 作者: Y. Takasaki;K. Kaneda;M. Matsushita;Hirofumi Yamada;M. Nawata;R. Matsudaira;M. Asano;R. Mineki;N. Shindo;H. Hashimoto

Glyleraldehyde 3-phosphate dehydrogenase is a novel autoantigen leading autoimmune responses to proliferating cell nuclear antigen nuclear antigen multiprotein complexs in lupus patients.

甘油醛 3-磷酸脱氢酶是一种新型自身抗原，可导致狼疮患者对增殖细胞核抗原核抗原多蛋白复合物产生自身免疫反应。

• 发表时间: 2004
• 期刊: lnt Immunol 16
• 作者: Takasaki Y;Kaneda K;Matsushita M;Yamada H;et al.
• 通讯作者: et al.

Autoimmune response to proteasome activator 28α in patients with connective tissue diseases.

结缔组织疾病患者对蛋白酶体激活剂 28α 的自身免疫反应。

• 发表时间: 2004
• 期刊: J.Rheumatol 31
• 作者: Matsushita M;Takasaki Y;Takeuchi K;et al.
• 通讯作者: et al.

Autoimmune response to proteins of proliferating cell nuclear antigen (PCNA) multiprotein complexes in patients with connective tissue diseases

结缔组织疾病患者对增殖细胞核抗原（PCNA）多蛋白复合物的自身免疫反应

• 发表时间: 2004
• 期刊: J.Rheumatol 31
• 作者: Kaneda k;Takasaki Y;Takeuchi K;et al.
• 通讯作者: et al.