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

对病毒病原体的免疫关键依赖于诱导细胞自主的I型干扰素反应，以及主要组织相容性I类(MHC)I类分子将病毒抗原呈递给适应性免疫系统的细胞。重要的是，由MHC-I类限制性抗原提呈介导的细胞毒性T细胞反应在消除恶性转化细胞中也起着重要作用。我们最近发现，人类NLRC5蛋白参与了I型干扰素应答的增加，以及MHC-I类基因表达的调节。这两种功能可能依赖于NLRC5在胞浆和胞核中不同的亚细胞定位。值得注意的是，这种先天免疫调节蛋白的双重特异性是非常独特的，这使得NLRC5成为一个非常有趣的研究蛋白质。NLRC5是“核苷酸结合结构域，富含亮氨酸重复序列的蛋白”(NLR)家族的成员。众所周知，这个家族的许多成员在人类的先天和获得性免疫反应中发挥着重要作用。值得注意的是，对于NLR成员，MHC II类转录激活因子(CIITA)，众所周知，NLR是MHC II类基因表达的主要调节者。据推测，可能存在类似的驱动MHC I类基因表达的因素。我们最近的结果表明，NLRC5是这种长期受到追捧的蛋白质，它驱动MHC I类基因的表达。虽然，NLRC5在I型干扰素反应和MHC-I类基因调控中的确切功能目前仍很难确定。申请人的实验室对人类NLR蛋白功能的分子特征有着长期的研究兴趣。在此，我们请求资助一项旨在破译NLRC5在抗病毒细胞自主应答和MHC I类基因表达调控中作用的详细分子机制的项目。此外，我们将讨论NLRC5在CD8 T细胞介导的病毒感染和转化细胞杀伤中的作用。该项目的反结果将为免疫的基本过程提供重要的新见解，特别是对MHC I类基因表达的调节。

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.