Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, 100005 Beijing, China.
Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, 100021 Beijing, China.
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23695-23706. doi: 10.1073/pnas.2003932117. Epub 2020 Sep 9.
Long noncoding RNAs (lncRNAs) involved in the regulation of antiviral innate immune responses need to be further identified. By functionally screening the lncRNAs in macrophages, here we identified lncRNA , abundant in the nucleus but significantly down-regulated after viral infection, as a negative regulator of antiviral type I IFN (IFN-I) production. directly bound to the transactive response DNA-binding protein (TDP43) in the nucleus and prevented activation of TDP43 by blocking the activated caspase-3-mediated TDP43 cleavage to TDP35. The cleaved TDP35 increased the nuclear IRF3 protein level by binding and degrading pre-mRNA to prevent IRF3 proteasomal degradation upon viral infection, thus selectively promoting antiviral IFN-I production. Deficiency of enhanced antiviral innate responses in vivo, accompanying the increased IFN-I production and reduced viral burden. Importantly, the reduced , augmented IRF3, and increased mRNA were found in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients. Therefore, the down-regulation of in virus-infected cells or in human cells from autoimmune diseases will increase host resistance against viral infection or lead to autoinflammatory interferonopathies via the increased type I IFN production. Our results demonstrate that the nuclear suppresses antiviral innate responses by targeting TDP43 activation via RNA-RBP interactive network, adding insight to the molecular regulation of innate responses and autoimmune pathogenesis.
长链非编码 RNA（lncRNA）在抗病毒先天免疫反应的调控中需要进一步鉴定。通过对巨噬细胞中的 lncRNA 进行功能筛选，我们在这里鉴定了一种 lncRNA，它在细胞核中丰富，但在病毒感染后显著下调，作为抗病毒 I 型 IFN（IFN-I）产生的负调节剂。lncRNA 直接与核内反式激活反应 DNA 结合蛋白（TDP43）结合，并通过阻断激活的 caspase-3 介导的 TDP43 切割为 TDP35 来阻止 TDP43 的激活。切割的 TDP35 通过结合和降解 pre-mRNA 来增加核 IRF3 蛋白水平，从而防止病毒感染时 IRF3 的蛋白酶体降解，从而选择性地促进抗病毒 IFN-I 的产生。lncRNA 缺失增强了体内抗病毒先天反应，伴随着 IFN-I 产生增加和病毒载量减少。重要的是，在系统性红斑狼疮（SLE）患者的外周血单核细胞（PBMC）中发现了减少的 、增加的 IRF3 和增加的 mRNA。因此，感染病毒的细胞或自身免疫性疾病患者的 下调会通过增加 I 型 IFN 的产生增加宿主对病毒感染的抵抗力或导致自身炎症性干扰素病。我们的研究结果表明，核 通过 RNA-RBP 相互作用网络靶向 TDP43 激活来抑制抗病毒先天反应，为先天反应和自身免疫发病机制的分子调控提供了新的见解。
