Mechanism and function of membrane trafficking in dendritic cells

项目摘要/摘要 树突状细胞在诱导抗原特异性免疫反应中发挥重要作用 将抗原呈递给幼稚的T细胞，并将其分化为特定的效应细胞。这一功能深刻地体现了 依赖于膜蛋白的适当运输，但支配特定分子机制的 人口贩运还没有完全被理解。我们的实验室感兴趣的是细胞内的运输 膜蛋白在树突状细胞功能中发挥重要作用。我们目前的研究主要集中在 了解泛素连接酶介导的膜转运的机制和功能 膜相关RIGN-CH1(3月1日)。March1将泛素链连接到细胞质的尾部 MHCII和CD86，这种泛素化诱导内吞作用、溶酶体分选和 分子。我们先前已经发现，树突状细胞需要依赖于March1的MHCII泛素化 选择调节性T细胞的细胞功能。其作用机制与March1泛素连接酶活性有关 在维持树突状细胞质膜上的MHCII蛋白稳定方面，这对树突状细胞至关重要 细胞稳定地结合并激活未成熟胸腺细胞，以调节T细胞分化。我们会调查的 这种活性是否也支持树突状细胞诱导抗原特异性T细胞免疫的功能。在……里面 此外，我们将在树突状细胞中鉴定March1的新底物，并询问分子 参与3月1日S泛素连接酶活性的相互作用。从这些研究中获得的信息不会 仅对树突状细胞中March1依赖的膜转运的作用提供了重要的新见解 这不仅提高了我们对膜蛋白泛素化机制的理解。

Project summary/abstract Dendritic cells play an important role in inducing antigen-specific immune responses through the ability to present antigens to naïve T cells and differentiate them to specific effector cells. This function is profoundly dependent on proper trafficking of membrane proteins, but the molecular mechanisms that govern the specific trafficking is not completely understood. Our laboratory is interested in characterizing intracellular trafficking of membrane proteins playing essential role in dendritic cell function. Our current research is focused on understanding the mechanism and function of the membrane trafficking mediated by a ubiquitin ligase named membrane associated RIGN-CH1 (MARCH1). MARCH1 attaches a ubiquitin chain to the cytoplasmic tail of MHCII and CD86, and this ubiquitination induces endocytosis, lysosomal sorting, and degradation of the molecules. We have previously found that MARCH1-dependent MHCII ubiquitination is required for dendritic cell function of selecting regulatory T cells. The mechanisms involved the ubiquitin ligase activity of MARCH1 in maintaining MHCII proteostasis in the plasma membrane of dendritic cells, which was crucial for dendritic cells to stably engage and activate immature thymocytes for regulatory T cell differentiation. We will investigate whether this activity also supports dendritic cell function of inducing antigen-specific T cell immunity. In addition, we will identify new substrates of MARCH1 in dendritic cells and interrogate the molecular interactions involved in MARCH1’s ubiquitin ligase activity. The information gained from these studies will not only provide important new insights into the role of MARCH1-dependent membrane trafficking in dendritic cell function but also improve our understanding on the mechanisms of membrane protein ubiquitination.