Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China.
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
J Autoimmun. 2022 Jun;130:102840. doi: 10.1016/j.jaut.2022.102840. Epub 2022 May 19.
Cell death is important in the elimination of damaged cells such as virus-infected cells and also is closely involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). The retinoic acid-inducible gene-I (RIG-I), one cytosolic RNA innate sensor, can trigger antiviral innate response by inducing production of type I interferons (IFN-I). However, the function of RIG-I, once translocated from cytoplasm to nucleus at the late stage of viral infection when IFN-I production is almost terminated, remains poorly understood. Here, we reported that RIG-I is accumulated in the nucleus of macrophages and fibroblasts after virus infection, and nuclear RIG-I is present in peripheral blood mononuclear cells (PBMCs) from SLE patients. We found that nuclear RIG-I interacts with the first 20 amino acids of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) and attenuates the anti-apoptotic properties of APEX1, therefore promoting apoptosis of virus-infected cells to suppress viral infection through an IFN-I-independent way at the late stage of viral infection. Together, our findings reveal a non-canonical role of nuclear RIG-I in the induction of cellular apoptosis, besides its activation of IFN-I expression as the cytosolic innate sensor. This study provides new insight to the regulation of infection, IFN-I and autoimmune diseases by nuclear RIG-I-APEX1 interaction.
细胞死亡对于清除病毒感染细胞等受损细胞非常重要，也与系统性红斑狼疮（SLE）等自身免疫性疾病的发病机制密切相关。维甲酸诱导基因-I（RIG-I）是一种细胞质 RNA 先天传感器，可通过诱导 I 型干扰素（IFN-I）的产生来触发抗病毒先天反应。然而，在病毒感染后期 IFN-I 产生几乎终止时，RIG-I 一旦从细胞质易位到细胞核，其功能仍知之甚少。在这里，我们报道 RIG-I 在病毒感染后在巨噬细胞和成纤维细胞的核内积累，并且核 RIG-I 存在于 SLE 患者的外周血单核细胞（PBMC）中。我们发现核 RIG-I 与脱嘌呤/脱嘧啶内切核酸酶 1（APEX1）的前 20 个氨基酸相互作用，并削弱了 APEX1 的抗凋亡特性，从而通过 IFN-I 非依赖性方式促进病毒感染细胞的凋亡，以在病毒感染后期抑制病毒感染。总之，我们的研究结果揭示了核 RIG-I 在诱导细胞凋亡中的非典型作用，除了作为细胞质先天传感器激活 IFN-I 表达之外。这项研究为核 RIG-I-APEX1 相互作用对感染、IFN-I 和自身免疫性疾病的调控提供了新的见解。
