Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS.
Chikungunya virus antagonizes cGAS-STING mediated type-I interferon responses by degrading cGAS.
复制标题
Chikungunya病毒通过降解CGA来拮抗CGAS插入介导的I型干扰素反应。
DOI：
10.1371/journal.ppat.1008999
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发表时间：
2020-10
期刊：
影响因子：
6.7
通讯作者：
Fernandez-Sesma A
中科院分区：
文献类型：
--
作者：
Webb LG;Veloz J;Pintado-Silva J;Zhu T;Rangel MV;Mutetwa T;Zhang L;Bernal-Rubio D;Figueroa D;Carrau L;Fenutria R;Potla U;Reid SP;Yount JS;Stapleford KA;Aguirre S;Fernandez-Sesma A
基孔肯雅病毒（CHIKV）是一种蚊媒甲病毒，已知可引起流行，导致主要有症状的感染，在极少数情况下导致长期衰弱性关节炎和关节痛。在了解典型RNA传感途径在CHIKV宿主识别中的作用方面取得了重大进展；然而，胞质DNA感应途径如环GMP-AMP合成酶（cGAS）和干扰素基因刺激因子（STING）对CHIKV的拮抗作用尚不清楚。通过使用cGAS或STING空细胞，我们证明了该途径限制了CHIKV在成纤维细胞和免疫细胞中的复制。我们发现DNA在感染细胞的细胞质中积累，并且CHIKV阻断DNA依赖性IFN-β转录。这种DNA感应的拮抗作用是通过早期自噬介导的cGAS降解，CHIKV衣壳蛋白的表达足以诱导cGAS降解。此外，我们确定了CHIKV nsP1与STING的相互作用，并将这种相互作用定位到接头蛋白细胞质环的23个残基上。这种相互作用稳定了病毒蛋白并增加了细胞中棕榈酰化nsP1的水平。总之，这项工作支持了先前的出版物，强调了cGAS-STING途径在（+）ssRNA病毒早期检测中的相关性，并提供了CHIKV与cGAS-STING信号相互作用并拮抗的直接证据。基孔肯雅病毒（CHIKV）是一种新出现的媒介传播病毒，可引起疫情，在人群中迅速传播。该病毒已被证明对i型干扰素信号非常敏感，可以阻断这种抗病毒途径。目前还没有研究确定CHIKV是否能够通过拮抗细胞质DNA感应来阻断i型IFN的诱导。在这里，我们发现CHIKV诱导DNA在感染细胞的细胞质中积累，并且病毒通过降解cGAS来阻断cGAS- sting依赖的先天免疫感知。这项工作首次描述了CHIKV介导的DNA依赖性先天免疫感知的抑制，并通过鉴定和表征另一种能够抵消cGAS-STING介导的DNA感知的RNA病毒家族，扩展了我们之前的工作。
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-β transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling. Chikungunya virus (CHIKV) is an emerging vector-borne virus which causes outbreaks that spread within populations quickly. The virus has been shown to be highly susceptible to type-I interferon signaling and can block this antiviral pathway. No work has identified if CHIKV is able to block the induction of type-I IFN by antagonizing cytosolic DNA sensing. Here we show that CHIKV induces the accumulation of DNA in the cytoplasm of infected cells and that the virus blocks cGAS-STING dependent innate immune sensing via degradation of cGAS. This work provides the first description of CHIKV mediated inhibition of DNA dependent innate immune sensing and expands upon our previous works by identifying and characterizing another RNA virus family able to counteract cGAS-STING mediated DNA sensing.
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