Characterization of the role of NLRC5 in immune responses and malignant transformation

NLRC5 在免疫反应和恶性转化中作用的表征

• 批准号: 226249835
• 负责人: Professor Dr. Thomas Kufer
• 金额: --
• 依托单位: Fachgebiet Immunologie (180b)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226249835?language=en
• 关键词: Characterization; role; NLRC5; immune; responses

Immunity towards viral pathogens pivotally depends on induction of cell-autonomous type I interferon responses and on presentation of viral antigen by major histocompatibility class I (MHC class I) mole-cules to cells of the adaptive immune system. Importantly, cytotoxic T cell responses mediated by MHC class I restricted antigen presentation also play an important role in the elimination of malignant transformed cells. We recently showed that the human NLRC5 protein is involved in mounting type I interferon respons-es, as well as in the regulation of MHC class I gene expression. These two functions likely depend on the differential sub-cellular localization of NLRC5 in the cytosol and the nucleus. Of note, such a dual specificity for an innate immune regulatory protein is quite unique, making NLRC5 a very interesting protein to study.NLRC5 is a member of the "nucleotide-binding domain, leucine rich repeat containing protein" (NLR) family. Many members of this family are ell known to play import roles in innate and adaptive immune responses in humans. Of note, for the NLR-member, MHC class II transcriptional activator (CIITA), it is well established that this NLR acts as the master regulator of MHC class II gene expression. It was speculated that a similar factor that drives MHC class I gene expression might exist. Our recent results suggest that NLRC5 is this long sought-after protein that drives MHC class I gene expression. Although, the exact function of NLRC5 both in the regulation of type I interferon responses and MHC class I gene regulation still remains largely elusive at present. The laboratory of the applicant has a long standing research interesting in the molecular characteriza-tion of the function of human NLR proteins. Here, we request funding of a project aiming to decipher the detailed molecular mechanisms underlying the role of NLRC5 in anti-viral cell-autonomous re-sponses and in the regulation of MHC class I gene expression. Furthermore, we will address the role of NLRC5 in CD8 T cell mediated killing of virus-infected and transformed cells.Anticipated results of this project will provide important novel insights into fundamental processes of immunity, in particular the regulation of the expression of MHC class I genes.

对病毒病原体的免疫主要取决于细胞自主性I型干扰素应答的诱导和主要组织相容性I类（MHC I类）分子向适应性免疫系统细胞呈递病毒抗原。重要的是，由MHC I类限制性抗原呈递介导的细胞毒性T细胞应答在恶性转化细胞的消除中也起重要作用。我们最近发现，人NLRC 5蛋白参与了I型干扰素应答的启动，以及MHC I类基因表达的调节。这两种功能可能取决于NLRC 5在细胞质和细胞核中的差异亚细胞定位。值得注意的是，这种对先天免疫调节蛋白的双重特异性是非常独特的，使得NLRC 5成为研究的非常有趣的蛋白质。NLRC 5是“核苷酸结合结构域，富含亮氨酸重复序列的蛋白质”（NLR）家族的成员。众所周知，该家族的许多成员在人类的先天性和适应性免疫应答中发挥重要作用。值得注意的是，对于NLR成员，MHC II类转录激活因子（CIITA），已经确定该NLR充当MHC II类基因表达的主调节因子。据推测，可能存在驱动MHC I类基因表达的类似因子。我们最近的研究结果表明，NLRC 5是一种长期受欢迎的蛋白质，可以驱动MHC I类基因的表达。尽管如此，NLRC 5在I型干扰素应答和MHC I类基因调控中的确切功能目前仍然很难确定。申请人的实验室长期致力于人NLR蛋白功能的分子表征研究。在这里，我们请求资助一个项目，旨在破译NLRC 5在抗病毒细胞自主反应和调节MHC I类基因表达中作用的详细分子机制。此外，我们还将探讨NLRC 5在CD8 T细胞介导的病毒感染和转化细胞杀伤中的作用，该项目的预期结果将为免疫的基本过程，特别是MHC I类基因表达的调控提供重要的新见解。