Molecular cell biology of MHC class I retention by the gp40 protein of the murine cytomegalovirus

鼠巨细胞病毒 gp40 蛋白保留 MHC I 类的分子细胞生物学

• 批准号: 287481932
• 负责人: Professor Dr. Sebastian Springer
• 金额: --
• 依托单位: Department of Life Sciences and Chemistry
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/287481932?language=en
• 关键词: Molecular; cell; biology; MHC; class

MHC (major histocompatibility complex) class I molecules play a key role in the anti-viral immune response by presenting viral antigens to cytotoxic T lymphocytes at the cell surface, which leads to apoptosis of the infected cell and to the control of infection. It is therefore not astonishing that many viruses have developed strategies to circumvent recognition by MHC class I molecules in order to persist: A vast number of viral proteins exist that interfere with antigen presentation, the so-called immunoevasins. We have been studying the immunoevasin gp40 of the murine cytomegalovirus (MCMV) and found out that its mode of action differs from that one of other immunoevasins: It binds to MHC class I molecules but, unlike other immunoevasins that interact directly, it does not lead to their degradation, instead, fully mature class I molecule are retained in an early compartment of the secretory pathway unable to reach the cell surface. We have further identified a novel sequence in gp40, the linker, which is required for both its own retention and that one of MHC class I molecules. These data are already summarized in a manuscript and will be submitted to publication soon. In this project, we will investigate the prerequisite for gp40-mediated class I intracellular retention, namely, the intracellular retention of gp40 itself: We will describe the kind of retention taking place, determine the function of the linker sequence in the retention process, and identify potential binding partners of gp40 that might regulate gp40 retention and, hence, its function. We will also investigate in detail the interaction between gp40 and class I in live cells. A more profound understanding of gp40 retention will help to shed light on the diversity of viral immune evasion strategies that are responsible for lifelong viral persistence.

MHC（主要组织相容性复合体）I类分子通过将病毒抗原提呈给细胞表面的细胞毒性T淋巴细胞，导致感染细胞凋亡并控制感染，在抗病毒免疫反应中发挥关键作用。因此，许多病毒为了生存而发展出规避MHC I类分子识别的策略并不奇怪：存在大量干扰抗原呈递的病毒蛋白，即所谓的免疫evasins。我们一直在研究小鼠巨细胞病毒（MCMV）的免疫evasin gp40，发现它的作用模式与其他免疫evasins不同：它与MHC I类分子结合，但与其他直接相互作用的免疫evasins不同，它不会导致它们的降解，相反，完全成熟的I类分子保留在分泌途径的早期隔室中，无法到达细胞表面。我们进一步确定了gp40中的一个新序列，即接头，它是其自身保留和MHC I类分子保留所必需的。这些数据已经汇总在一份手稿中，不久将提交出版。在这个项目中，我们将调查gp40介导的I类细胞内滞留的先决条件，即gp40本身的细胞内滞留：我们将描述发生的滞留类型，确定在滞留过程中的连接序列的功能，并确定潜在的gp40的结合伙伴，可能会调节gp40的滞留，因此，它的功能。我们还将详细研究活细胞中gp40和I类之间的相互作用。对gp40保留的更深刻理解将有助于揭示病毒免疫逃避策略的多样性，这些策略是终身病毒持续存在的原因。