IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation.
RNA virus infection is recognized by the RIG-I family of receptors that activate the mitochondrial adaptor MAVS, leading to the clearance of viruses. Antiviral signalling activation requires strict modulation to avoid damage to the host from exacerbated inflammation. Insulin receptor tyrosine kinase substrate (IRTKS) participates in actin bundling and insulin signalling and its deficiency causes insulin resistance. However, whether IRTKS is involved in the regulation of innate immunity remains elusive. Here we show that IRTKS deficiency causes enhanced innate immune responses against RNA viruses. IRTKS-mediated suppression of antiviral responses depends on the RIG-I-MAVS signalling pathway. IRTKS recruits the E2 ligase Ubc9 to sumoylate PCBP2 in the nucleus, which causes its cytoplasmic translocation during viral infection. The sumoylated PCBP2 associates with MAVS to initiate its degradation, leading to downregulation of antiviral responses. Thus, IRTKS functions as a negative modulator of excessive inflammation.
Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.
Pengyan
P
Xia
Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.
Shuo
S
Wang
Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.|University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
Zhen
Z
Xiong
Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.
Buqing
B
Ye
Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China.
Li-Yu
LY
Huang
Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China.
Ze-Guang
ZG
Han
Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.|University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
Zusen
Z
Fan
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D064113:CRISPR-Cas Systems; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007113:Immunity, Innate / Q000235:genetics* / Q000276:immunology; D047468:Immunoprecipitation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics* / Q000276:immunology; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018353:Rhabdoviridae Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D058207:Sumoylation; D044763:Ubiquitin-Conjugating Enzymes / Q000276:immunology / Q000378:metabolism*; D018116:Vesiculovirus; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D008840:Microfilament Proteins; D016601:RNA-Binding Proteins; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9; C512612:MAVS protein, mouse; C000606831:IRTKS protein, mouse; C501904:Pcbp2 protein, mouse; C503356:Ddx58 protein, mouse