TRIM29 promotes DNA virus infections by inhibiting innate immune response.
TRIM29 promotes DNA virus infections by inhibiting innate immune response.
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DOI：
10.1038/s41467-017-00101-w
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发表时间：
2017-10-16
影响因子：
16.6
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Xing J;Zhang A;Zhang H;Wang J;Li XC;Zeng MS;Zhang Z
许多双链DNA病毒，如EB病毒，可以建立持续感染，但潜在的病毒-宿主相互作用仍然知之甚少。在这里，我们报告说，在人类气道上皮细胞中，EB病毒诱导TRIM 29，TRIM蛋白家族的成员，抑制先天免疫激活。在气道上皮细胞中TRIM 29的敲低增强I型干扰素的产生，并且在人鼻咽癌细胞中导致几乎完全的EB病毒清除。TRIM 29也被髓样树突细胞中的胞质双链DNA高度诱导。TRIM 29 −/−小鼠在肺中具有较低的腺病毒滴度，并且由于I型干扰素的产生增加而对致命的单纯疱疹病毒-1感染具有抗性。TRIM 29诱导K48连接的干扰素刺激因子基因的泛素化，这是双链DNA传感途径中的关键衔接子，随后其快速降解。这些数据表明，爱泼斯坦-巴尔病毒和其他可能的双链DNA病毒使用TRIM 29来抑制局部先天免疫，导致DNA病毒感染的持续性。TRIM家族的蛋白质在免疫信号传导中具有调节功能，通常通过靶蛋白的泛素化。在这里，作者表明TRIM 29在感染DNA病毒后被诱导，导致STING降解，干扰素信号传导减少，小鼠致病性增加。
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.
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