Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Department of Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo, Japan.
J Biol Chem. 2024 May;300(5):107205. doi: 10.1016/j.jbc.2024.107205. Epub 2024 Mar 20.
Major histocompatibility complex (MHC) class I molecules play an essential role in regulating the adaptive immune system by presenting antigens to CD8 T cells. CITA (MHC class I transactivator), also known as NLRC5 (NLR family, CARD domain-containing 5), regulates the expression of MHC class I and essential components involved in the MHC class I antigen presentation pathway. While the critical role of the nuclear distribution of NLRC5 in its transactivation activity has been known, the regulatory mechanism to determine the nuclear localization of NLRC5 remains poorly understood. In this study, a comprehensive analysis of all domains in NLRC5 revealed that the regulatory mechanisms for nuclear import and export of NLRC5 coexist and counterbalance each other. Moreover, GCN5 (general control non-repressed 5 protein), a member of HATs (histone acetyltransferases), was found to be a key player to retain NLRC5 in the nucleus, thereby contributing to the expression of MHC class I. Therefore, the balance between import and export of NLRC5 has emerged as an additional regulatory mechanism for MHC class I transactivation, which would be a potential therapeutic target for the treatment of cancer and virus-infected diseases.
主要组织相容性复合体（MHC）I 类分子通过将抗原呈递给 CD8 T 细胞，在调节适应性免疫系统方面发挥着重要作用。CITA（MHC I 类转激活物），也称为 NLRC5（NLR 家族，CARD 结构域包含 5），调节 MHC I 类的表达和 MHC I 类抗原呈递途径中涉及的必需成分。尽管 NLRC5 的核分布在其转录激活活性中的关键作用已经众所周知，但决定 NLRC5 核定位的调节机制仍知之甚少。在这项研究中，对 NLRC5 所有结构域的全面分析表明，NLRC5 的核输入和输出的调节机制并存且相互制衡。此外，发现 GCN5（一般控制非抑制 5 蛋白），一种 HATs（组蛋白乙酰转移酶）的成员，是将 NLRC5 保留在核内的关键因素，从而有助于 MHC I 类的表达。因此，NLRC5 的输入和输出之间的平衡已成为 MHC I 类转录激活的另一种调节机制，这可能成为治疗癌症和病毒感染性疾病的潜在治疗靶点。
