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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Heat-shock protein 90 associates with N-terminal extended peptides and is required for direct and indirect antigen presentation
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Heat-shock protein 90 associates with N-terminal extended peptides and is required for direct and indirect antigen presentation

机译：热休克蛋白90与N末端延伸肽缔合，是直接和间接抗原呈递的必需条件

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摘要

CD8~+ T cells recognize peptide fragments of endogenously synthesized antigens of cancers or viruses, presented by MHC I molecules. Such antigen presentation requires the generation of peptides in the cytosol, their passage to the endoplasmic reticulum, loading of MHC I with peptides, and transport of MHC l-peptide complexes to the cell surface. Heat-shock protein (hsp) 90 is a cytosolic chaperone known to associate with peptide and peptide precursors of MHC I epitopes. We report here that treatment of cells with hsp90 inhibitors leads to generation of "empty" MHC I caused by inhibited loading of MHC I with peptides. Inhibition of hsp90 does not inhibit synthesis of MHC I, nor does it affect the activity of proteasomes. Hsp90-inhibited cells, such as proteasome-inhibited cells, are poor stimulators of T lymphocytes. The role of hsp90 in presentation of an ovalbumin epitope is shown to be at a postproteasomal step: hsp90 associates with N-terminally extended precursors of the SIINFEHL epitope, and such peptides are depleted from hsp90 preparations in hsp90-inhibited cells. Inhibition of hsp90 in the antigen donor cell compromises their ability to cross-prime. Conversely, stressed cells expressing elevated hsp90 levels show a heat-shock factor-dependent, enhanced ability to cross-prime. These results demonstrate a substantial role for hsp90 in chaperoning of antigenic peptides in direct and indirect presentation. The introduction of a stress-inducible component in these pathways has significant implications for their modulation during fever and infection.
机译：CD8 + T细胞识别由MHC I分子呈递的内源性合成癌症或病毒抗原的肽片段。这样的抗原呈递需要在胞质溶胶中产生肽，将它们传递到内质网，用肽装载MHC I，以及将MHC 1-肽复合物转运到细胞表面。热休克蛋白（hsp）90是已知与MHC I表位的肽和肽前体缔合的胞质伴侣。我们在这里报告说，用hsp90抑制剂处理细胞会导致“空” MHC I的产生，这是由于MHC I的肽负载受抑制引起的。抑制hsp90不会抑制MHC I的合成，也不会影响蛋白酶体的活性。 Hsp90抑制的细胞，如蛋白酶体抑制的细胞，是T淋巴细胞的弱刺激物。 hsp90在卵清蛋白表位呈递中的作用显示在蛋白酶体后步骤：hsp90与SIINFEHL表位的N端延伸前体缔合，并且这种肽从hsp90抑制细胞中的hsp90制剂中耗尽。 hsp90在抗原供体细胞中的抑制会损害其交叉启动能力。相反，表达升高的hsp90水平的应激细胞显示出依赖于热休克因子的增强的交叉引物能力。这些结果证明了hsp90在直接和间接呈递抗原肽的伴侣中的重要作用。在这些途径中引入压力诱导成分对其在发烧和感染期间的调节具有重要意义。

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