SARS-CoV-2 spike protein-induced cell fusion activates the cGAS-STING pathway and the interferon response
SARS-CoV-2 spike protein-induced cell fusion activates the cGAS-STING pathway and the interferon response
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DOI：
10.1126/scisignal.abg8744
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发表时间：
2022-04-12
影响因子：
7.3
通讯作者：
Guo, Fei
中科院分区：
文献类型：
--
作者：
Liu, Xiaoman;Wei, Liang;Guo, Fei
严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）引发了前所未有的2019冠状病毒病（COVID-19）大流行。COVID-19危重病例的特征是产生过量的细胞因子和广泛的肺损伤，这部分是由sars - cov -2感染的肺细胞融合引起的。在这里，我们发现由SARS-CoV-2刺突(S)蛋白引起的细胞融合诱导了I型干扰素（IFN）反应。S蛋白的这种功能需要蛋白酶在S1/S2和S2'位点进行切割。我们进一步发现，细胞融合破坏细胞核并导致微核的形成，这些微核被细胞质DNA传感器cGAS感知，并导致其下游效应物STING的激活。在缺乏cgas的融合细胞中，转录调节因子IRF3的磷酸化和编码I型IFN的IFNB的表达被取消。此外，感染VSV-SARS-CoV-2还会诱导细胞融合、DNA损伤和依赖cgas - sting的IFNB表达。总之，这些结果揭示了IFN对SARS-CoV-2感染反应的潜在途径。我们的数据表明，COVID-19患者肺部融合的肺细胞可能会增强ifn和其他细胞因子的产生，从而加剧疾病的严重程度。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the unprecedented coronavirus disease 2019 (COVID-19) pandemic. Critical cases of COVID-19 are characterized by the production of excessive amounts of cytokines and extensive lung damage, which is partially caused by the fusion of SARS-CoV-2-infected pneumocytes. Here, we found that cell fusion caused by the SARS-CoV-2 spike (S) protein induced a type I interferon (IFN) response. This function of the S protein required its cleavage by proteases at the S1/S2 and the S2' sites. We further showed that cell fusion damaged nuclei and resulted in the formation of micronuclei that were sensed by the cytosolic DNA sensor cGAS and led to the activation of its downstream effector STING. Phosphorylation of the transcriptional regulator IRF3 and the expression of IFNB, which encodes a type I IFN, were abrogated in cGAS-deficient fused cells. Moreover, infection with VSV-SARS-CoV-2 also induced cell fusion, DNA damage, and cGAS-STING-dependent expression of IFNB. Together, these results uncover a pathway underlying the IFN response to SARS-CoV-2 infection. Our data suggest a mechanism by which fused pneumocytes in the lungs of patients with COVID-19 may enhance the production of IFNs and other cytokines, thus exacerbating disease severity.