分类： 生物学 >> 生物物理学 >> 免疫学 提交时间： 2016-05-12
Chen, Jun
Hao, Lu
Li, Chong
Ye, Buqing
Du, Ying
Zhang, Honglian
Zhu, Pingping
Liu, Benyu
Yang, Liuliu
Fan, Zusen
Chen, Jun
Hao, Lu
Long, Bo
Long, Bo
Li, Peifeng
Tian, Yong
摘要： NK cells play a pivotal role in innate immune responses against pathogenic infections. However, the underlying mechanisms driving defined NK functions remain largely elusive. In this study, we identified a novel endoplasmic reticulum (ER) membrane protein, ER adaptor protein (ERAdP), which is constitutively expressed in human and mouse NK cells. ERAdP is expressed at low levels in peripheral NK cells of hepatitis B virus-associated hepatocellular carcinoma patients. We show that ERAdP initiates NK cell activation through the NF-kappa B pathway. Notably, ERAdP interacts with ubiquitin-conjugating enzyme 13 (Ubc13) to potentiate its charging activity. Thus, ERAdP augments Ubc13-mediated NF-kappa B essential modulator ubiquitination to trigger the Ubc13-mediated NF-kappa B pathway, leading to NK cell activation. Finally, ERAdP transgenic mice display hyperactivated NK cells that are more resistant to pathogenic infections. Therefore, understanding the mechanism of ERAdP-mediated NK cell activation will provide strategies for treatment of infectious diseases.
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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