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p204 和 cGAS DNA 传感器对小鼠多瘤病毒 DNA 的免疫感应。

Immune sensing of mouse polyomavirus DNA by p204 and cGAS DNA sensors.

机构信息

Department of Genetics and Microbiology, Faculty of Science, Charles University, Biocev, Czech Republic.

出版信息

FEBS J. 2021 Oct;288(20):5964-5985. doi: 10.1111/febs.15962. Epub 2021 May 26.

DOI:10.1111/febs.15962
PMID:33969628
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8596513/
Abstract

The mechanism by which DNA viruses interact with different DNA sensors and their connection with the activation of interferon (IFN) type I pathway are poorly understood. We investigated the roles of protein 204 (p204) and cyclic guanosine-adenosine synthetase (cGAS) sensors during infection with mouse polyomavirus (MPyV). The phosphorylation of IFN regulatory factor 3 (IRF3) and the stimulator of IFN genes (STING) proteins and the upregulation of IFN beta (IFN-β) and MX Dynamin Like GTPase 1 (MX-1) genes were detected at the time of replication of MPyV genomes in the nucleus. STING knockout abolished the IFN response. Infection with a mutant virus that exhibits defective nuclear entry via nucleopores and that accumulates in the cytoplasm confirmed that replication of viral genomes in the nucleus is required for IFN induction. The importance of both DNA sensors, p204 and cGAS, in MPyV-induced IFN response was demonstrated by downregulation of the IFN pathway observed in p204-knockdown and cGAS-knockout cells. Confocal microscopy revealed the colocalization of p204 with MPyV genomes in the nucleus. cGAS was found in the cytoplasm, colocalizing with viral DNA leaked from the nucleus and with DNA within micronucleus-like bodies, but also with the MPyV genomes in the nucleus. However, 2'3'-Cyclic guanosine monophosphate-adenosine monophosphate synthesized by cGAS was detected exclusively in the cytoplasm. Biochemical assays revealed no evidence of functional interaction between cGAS and p204 in the nucleus. Our results provide evidence for the complex interactions of MPyV and DNA sensors including the sensing of viral genomes in the nucleus by p204 and of leaked viral DNA and micronucleus-like bodies in the cytoplasm by cGAS.

摘要

DNA 病毒与不同 DNA 传感器相互作用的机制及其与 I 型干扰素（IFN）途径激活的关系尚不清楚。我们研究了蛋白 204（p204）和环鸟苷酸-腺苷酸合酶（cGAS）传感器在感染小鼠多瘤病毒（MPyV）时的作用。在 MPyV 基因组在核内复制时，检测到干扰素调节因子 3（IRF3）和干扰素基因刺激因子（STING）蛋白的磷酸化以及 IFN-β（IFN-β）和动力蛋白样 GTP 酶 1（MX-1）基因的上调。STING 敲除消除了 IFN 反应。感染一种通过核孔表现出缺陷性核进入并在细胞质中积累的突变病毒证实，病毒基因组在核内的复制是 IFN 诱导所必需的。通过在 p204 敲低和 cGAS 敲除细胞中观察到 IFN 途径的下调，证明了 p204 和 cGAS 这两种 DNA 传感器在 MPyV 诱导的 IFN 反应中的重要性。共聚焦显微镜显示 p204 与核内 MPyV 基因组共定位。cGAS 位于细胞质中，与从核内漏出的病毒 DNA 以及微核样体中的 DNA 共定位，但也与核内的 MPyV 基因组共定位。然而，cGAS 合成的 2'3'-环鸟苷酸单磷酸-腺苷酸单磷酸仅在细胞质中检测到。生化测定未发现 cGAS 和 p204 在核内存在功能相互作用的证据。我们的结果提供了证据，证明了 MPyV 和 DNA 传感器之间存在复杂的相互作用，包括 p204 对核内病毒基因组的感应以及细胞质中漏出的病毒 DNA 和微核样体的感应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0fd/8596513/816e992efb7a/FEBS-288-5964-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0fd/8596513/816e992efb7a/FEBS-288-5964-g006.jpg

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