Xing Junji, Zhang Ao, Zhang Hua, Wang Jin, Li Xian Chang, Zeng Mu-Sheng, Zhang Zhiqiang
Immunobiology and Transplant Science Center, Houston Methodist Research Institute, Houston, TX, 77030, USA.
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Nat Commun. 2017 Oct 16;8(1):945. doi: 10.1038/s41467-017-00101-w.
Many double-stranded DNA viruses, such as Epstein-Barr virus, can establish persistent infection, but the underlying virus-host interactions remain poorly understood. Here we report that in human airway epithelial cells Epstein-Barr virus induces TRIM29, a member of the TRIM family of proteins, to inhibit innate immune activation. Knockdown of TRIM29 in airway epithelial cells enhances type I interferon production, and in human nasopharyngeal carcinoma cells results in almost complete Epstein-Barr virus clearance. TRIM29 is also highly induced by cytosolic double-stranded DNA in myeloid dendritic cells. TRIM29 mice have lower adenovirus titers in the lung, and are resistant to lethal herpes simplex virus-1 infection due to enhanced production of type I interferon. Mechanistically, TRIM29 induces K48-linked ubiquitination of Stimulator of interferon genes, a key adaptor in double-stranded DNA-sensing pathway, followed by its rapid degradation. These data demonstrate that Epstein-Barr virus and possible other double-stranded DNA viruses use TRIM29 to suppress local innate immunity, leading to the persistence of DNA virus infections.Proteins of the TRIM family have regulatory functions in immune signaling, often via ubiquitination of target proteins. Here, the authors show that TRIM29 is induced upon infection with DNA viruses, resulting in degradation of STING, decreased interferon signaling and increased pathogenicity in mice.
许多双链DNA病毒，如爱泼斯坦-巴尔病毒，能够建立持续性感染，但其潜在的病毒-宿主相互作用仍知之甚少。在此我们报告，在人气道上皮细胞中，爱泼斯坦-巴尔病毒诱导TRIM家族蛋白成员之一的TRIM29，以抑制先天性免疫激活。在气道上皮细胞中敲低TRIM29可增强I型干扰素的产生，而在人鼻咽癌细胞中则几乎可完全清除爱泼斯坦-巴尔病毒。TRIM29在髓样树突状细胞中也可被胞质双链DNA高度诱导。TRIM29基因敲除小鼠肺部的腺病毒滴度较低，并且由于I型干扰素产生增加而对致死性单纯疱疹病毒1感染具有抗性。从机制上来说，TRIM29诱导干扰素基因刺激物（双链DNA感应途径中的关键衔接蛋白）发生K48连接的泛素化，随后其迅速降解。这些数据表明，爱泼斯坦-巴尔病毒以及可能的其他双链DNA病毒利用TRIM29来抑制局部先天性免疫，从而导致DNA病毒感染的持续性。TRIM家族蛋白通常通过对靶蛋白进行泛素化修饰在免疫信号传导中发挥调节功能。在此，作者表明TRIM29在感染DNA病毒后被诱导，导致干扰素基因刺激物降解、干扰素信号传导减少以及小鼠致病性增加。
