IRF3-binding lncRNA-ISIR strengthens interferon production in viral infection and autoinflammation
Junfang Xu,
Pin Wang,
Zemeng Li,
Zhiqing Li,
Dan Han,
Mingyue Wen,
Qihang Zhao,
Lianfeng Zhang,
Yuanwu Ma,
Wei Liu,
Minghong Jiang,
Xuan Zhang,
Xuetao Cao
Affiliations
Junfang Xu
Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
Pin Wang
National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China; Corresponding author
Zemeng Li
National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Zhiqing Li
National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Dan Han
Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Mingyue Wen
National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Qihang Zhao
National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China
Lianfeng Zhang
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing 100021, China
Yuanwu Ma
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing 100021, China
Wei Liu
Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
Minghong Jiang
Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China
Xuan Zhang
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
Xuetao Cao
Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Medical University, Shanghai 200433, China; Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences, Beijing 100021, China; Corresponding author
Summary: Interferon regulatory factor 3 (IRF3) is an essential transductor for initiation of many immune responses. Here, we show that lncRNA-ISIR directly binds IRF3 to promote its phosphorylation, dimerization, and nuclear translocation, along with enhanced target gene productions. In vivo lncRNA-ISIR deficiency results in reduced IFN production, uncontrolled viral replication, and increased mortality. The human homolog, AK131315, also binds IRF3 and promotes its activation. More important, AK131315 expression is positively correlated with type I interferon (IFN-I) level and severity in patients with lupus. Mechanistically, in resting cells, IRF3 is bound to suppressor protein Flightless-1 (Fli-1), which keeps its inactive state. Upon infection, IFN-I-induced lncRNA-ISIR binds IRF3 at DNA-binding domain in cytoplasm and removes Fli-1’s association from IRF3, consequently facilitating IRF3 activation. Our results demonstrate that IFN-I-inducible lncRNA-ISIR feedback strengthens IRF3 activation by removing suppressive Fli-1 in immune responses, revealing a method of lncRNA-mediated modulation of transcription factor (TF) activation.
