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Identification of Immunoproteasome dependent factors involved in cytokine release and T cell differentiation

鉴定参与细胞因子释放和 T 细胞分化的免疫蛋白酶体依赖性因子

基本信息

批准号：
237290469
负责人：
Professor Dr. Michael Basler
金额：
--
依托单位：
Lehrstuhl Biologie/Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/237290469?language=en
关键词：
Identification Immunoproteasome dependent factors involved

项目摘要

Cells of hematopoietic origin, particularly lymphocytes and monocytes, express the catalytic subunits of the immunoproteasome low-molecular mass polypeptide (LMP)2 (beta1i), LMP7 (beta5i), and multicatalytic endopeptidase complex subunit-1 (MECL-1) (beta2i) proteins. These three subunits can also be induced in non-hematopoietic cells after exposure to inflammatory cytokines. The immunoproteasome is known for its role in antigen processing along the MHC class I pathway. Recently, novel functions of immunoproteasomes in T cell proliferation, cytokine production, T cell differentiation, and autoimmune diseases have been discovered, but the underlying molecular mechanisms have remained elusive. In order to investigate how the immunoproteasome may be mechanistically involved in the control of T cell activation and cytokine production, several experimental approaches will be pursued. Transcription factors and signalling molecules known to be involved in T cell activation and interferon-gamma stimulation will be investigated with respect to their phosphorylation status and expression level in the presence and absence of an LMP7 inhibitor. In order to identify LMP7-dependent factors involved in cytokine production we will take advantage of two newly developed methods. We will quantitatively assess the ubiquitin-modified proteome in the presence or absence of LMP7-inhbition. Additionally, we intend to identify and quantify proteolytic events by terminal amine isotopic labelling of substrates in cells subjected to LMP7-inhibition. With these experiments we intend to investigate the central hypothesis that the immunoproteasome may selectively process or degrade a factor involved in cytokine production, T cell differentiation, and T cell activation.

造血来源的细胞，特别是淋巴细胞和单核细胞，表达免疫蛋白酶体低分子量多肽（LMP）2（β 1 i）、LMP 7（β 5 i）和多催化内肽酶复合物亚基-1（MECL-1）（β 2 i）蛋白的催化亚基。这三个亚基也可以在暴露于炎性细胞因子后在非造血细胞中被诱导。免疫蛋白酶体以其在沿着MHC I类途径的抗原加工中的作用而闻名。近年来，免疫蛋白酶体在T细胞增殖、细胞因子产生、T细胞分化和自身免疫性疾病中的新功能被发现，但其潜在的分子机制仍不清楚。为了研究免疫蛋白酶体如何在机械上参与T细胞活化和细胞因子产生的控制，将采用几种实验方法。将研究已知参与T细胞活化和干扰素-γ刺激的转录因子和信号分子在存在和不存在LMP 7抑制剂的情况下的磷酸化状态和表达水平。为了鉴定参与细胞因子产生的LMP 7依赖性因子，我们将利用两种新开发的方法。我们将定量评估泛素修饰的蛋白质组在存在或不存在LMP 7抑制。此外，我们打算确定和定量蛋白水解事件的终端胺同位素标记的底物在细胞受到LMP 7抑制。通过这些实验，我们打算研究中心的假设，免疫蛋白酶体可以选择性地处理或降解的因子参与细胞因子的产生，T细胞分化，T细胞活化。