Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China.
Frontiers Science Center for Cell Responses, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
Nat Commun. 2023 Dec 20;14(1):8455. doi: 10.1038/s41467-023-43784-0.
Innate sensors initiate the production of type I interferons (IFN-I) and proinflammatory cytokines to protect host from viral infection. Several innate nuclear sensors that mainly induce IFN-I production have been identified. Whether there exist innate nuclear sensors that mainly induce proinflammatory cytokine production remains to be determined. By functional screening, we identify 40 S ribosomal protein SA (RPSA) as a nuclear protein that recognizes viral nucleic acids and predominantly promotes proinflammatory cytokine gene expression in antiviral innate immunity. Myeloid-specific Rpsa-deficient mice exhibit less innate inflammatory response against infection with Herpes simplex virus-1 (HSV-1) and Influenza A virus (IAV), the viruses replicating in nucleus. Mechanistically, nucleus-localized RPSA is phosphorylated at Tyr204 upon infection, then recruits ISWI complex catalytic subunit SMARCA5 to increase chromatin accessibility of NF-κB to target gene promotors without affecting innate signaling. Our results add mechanistic insights to an intra-nuclear way of initiating proinflammatory cytokine expression in antiviral innate defense.
先天传感器启动 I 型干扰素 (IFN-I) 和促炎细胞因子的产生，以保护宿主免受病毒感染。已经鉴定出几种主要诱导 IFN-I 产生的先天核传感器。是否存在主要诱导促炎细胞因子产生的先天核传感器仍有待确定。通过功能筛选，我们鉴定出 40S 核糖体蛋白 SA (RPSA) 是一种核蛋白，可识别病毒核酸，并在抗病毒先天免疫中主要促进促炎细胞因子基因的表达。髓样细胞特异性 Rpsa 缺陷小鼠对单纯疱疹病毒-1 (HSV-1) 和甲型流感病毒 (IAV) 的感染表现出较低的先天炎症反应，这两种病毒在核内复制。在机制上，感染时核定位的 RPSA 在 Tyr204 处发生磷酸化，然后募集 ISWI 复合物催化亚基 SMARCA5 增加 NF-κB 对靶基因启动子的染色质可及性，而不影响先天信号。我们的研究结果为抗病毒先天防御中启动促炎细胞因子表达的核内途径提供了机制见解。
