Interferon-gamma inducible exchanges of 20S proteasome active site subunits: why?
Interferon-gamma inducible exchanges of 20S proteasome active site subunits: why?
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发表时间：
2001
期刊：
影响因子：
3.9
通讯作者：
M. Groettrup;S. Khan;K. Schwarz;G. Schmidtke
中科院分区：
文献类型：
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作者：
M. Groettrup;S. Khan;K. Schwarz;G. Schmidtke
当用细胞因子IFN-γ或TNF-α刺激细胞时，诱导三种蛋白酶体亚基LMP 2（β 1 i）、LMP 7（β 5 i）和MECL-1（β 2 i）的合成。在蛋白酶体新合成过程中，这些亚基取代了三个亚基delta（beta1）、MB 1（beta5）和Z（beta2），它们具有蛋白酶体的催化活性位点。甜菜碱诱导的三个活性位点亚基的一个复杂的蛋白酶的交换是前所未有的在生物学中，人们可能会期望一个强大的功能驱动力，这个系统的发展。据信，这些精氨酸诱导的蛋白酶体亚单位的替换有利于产生主要组织相容性复合体（MHC）I类分子的肽配体，用于刺激细胞毒性T细胞。尽管组成型蛋白酶体的肽生产能够在LMP 2和LMP 7不存在的情况下维持肽依赖性MHC I类细胞表面表达，但最近显示这些亚基对于几个独特表位的产生或破坏是关键的。在这篇综述中，我们讨论了LMP 2/LMP 7/MECL-1依赖的表位生成和这些亚基交换的功能的最新数据。我们提出，这些亚基交换不仅进化到优化I类肽加载，而且还在炎症部位产生LMP 2/LMP 7/MECL-1依赖性表位，这些表位在未发炎组织中不通过蛋白水解产生。这种表位产生的差异可能有助于更好地刺激正在进行的免疫应答部位的T细胞，并避免未发炎组织中的自身免疫。
When cells are stimulated with the cytokines IFN-gamma or TNF-alpha, the synthesis of three proteasome subunits LMP2 (beta1i), LMP7 (beta5i), and MECL-1 (beta2i) is induced. These subunits replace the three subunits delta (beta1), MB1 (beta5), and Z (beta2), which bear the catalytically active sites of the proteasome, during proteasome neosynthesis. The cytokine-induced exchanges of three active site subunits of a complex protease is unprecedented in biology and one may expect a strong functional driving force for this system to evolve. These cytokine-induced replacements of proteasome subunits are believed to favour the production of peptide ligands of major histocompatibility complex (MHC) class I molecules for the stimulation of cytotoxic T cells. Although the peptide production by constitutive proteasomes is able to maintain peptide-dependent MHC class I cell surface expression in the absence of LMP2 and LMP7, these subunits were recently shown to be pivotal for the generation or destruction of several unique epitopes. In this review we discuss the recent data on LMP2/LMP7/MECL-1-dependent epitope generation and the functions of each of these subunit exchanges. We propose that these subunit exchanges have evolved not only to optimize class I peptide loading but also to generate LMP2/LMP7/MECL-1-dependent epitopes in inflammatory sites which are not proteolytically generated in uninflamed tissues. This difference in epitope generation may serve to better stimulate T cells in the sites of an ongoing immune response and to avoid autoimmunity in uninflamed tissues.