分类： 生物学 >> 生物物理学 提交时间： 2016-05-12
Xia, Pengyan
Wang, Shuo
Xiong, Zhen
Ye, Buqing
Fan, Zusen
Xiong, Zhen
Fan, Zusen
Huang, Li-Yu
Han, Ze-Guang
Huang, Li-Yu
Han, Ze-Guang
Huang, Li-Yu
Han, Ze-Guang
摘要： 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.
分类： 生物学 >> 生物物理学 >> 免疫学 提交时间： 2016-05-05
Xia, Pengyan
Ye, Buqing
Wang, Shuo
Du, Ying
Xiong, Zhen
Fan, Zusen
Zhu, Xiaoxiao
Xiong, Zhen
Fan, Zusen
Tian, Yong
Tian, Yong
摘要： Cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA during viral infection and catalyzes synthesis of the dinucleotide cGAMP, which activates the adaptor STING to initiate antiviral responses. Here we found that deficiency in the carboxypeptidase CCP5 or CCP6 led to susceptibility to DNA viruses. CCP5 and CCP6 were required for activation of the transcription factor IRF3 and interferons. Polyglutamylation of cGAS by the enzyme TTLL6 impeded its DNA-binding ability, whereas TTLL4-mediated monoglutamylation of cGAS blocked its synthase activity. Conversely, CCP6 removed the polyglutamylation of cGAS, whereas CCP5 hydrolyzed the monoglutamylation of cGAS, which together led to the activation of cGAS. Therefore, glutamylation and deglutamylation of cGAS tightly modulate immune responses to infection with DNA viruses.
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