SARS-COV-2 protein NSP9 promotes cytokine production by targeting TBK1.
SARS-COV-2 protein NSP9 promotes cytokine production by targeting TBK1.
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DOI：
10.3389/fimmu.2023.1211816
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
SARS-COV-2感染引起的过度或不受控制的细胞因子风暴可能导致宿主组织损伤甚至死亡。然而，SARS-COV-2引起细胞因子风暴的机制尚不清楚。在这里，我们证明了SARS-COV-2蛋白NSP9通过与TANK-binding kinase-1 （TBK1）相互作用并激活TBK1来促进细胞因子的产生。通过rVSV-NSP9病毒感染模型，我们发现nsp9诱导的细胞因子风暴加重了小鼠的组织损伤和死亡。机制上，NSP9促进k63相关的泛素化和TBK1的磷酸化，从而诱导IRF3的激活和易位，从而增加下游细胞因子的产生。此外，E3泛素连接酶Midline 1 （MID1）促进了k48相关的NSP9泛素化和降解，而病毒感染抑制了MID1与NSP9的相互作用，从而抑制了NSP9的降解。此外，我们发现NSP9的Lys59是参与降解的关键泛素位点。这些发现阐明了SARS-COV-2蛋白促进细胞因子风暴的先前未知机制，并确定了COVID-19治疗的新靶点。
SARS-COV-2 infection-induced excessive or uncontrolled cytokine storm may cause injury of host tissue or even death. However, the mechanism by which SARS-COV-2 causes the cytokine storm is unknown. Here, we demonstrated that SARS-COV-2 protein NSP9 promoted cytokine production by interacting with and activating TANK-binding kinase-1 (TBK1). With an rVSV-NSP9 virus infection model, we discovered that an NSP9-induced cytokine storm exacerbated tissue damage and death in mice. Mechanistically, NSP9 promoted the K63-linked ubiquitination and phosphorylation of TBK1, which induced the activation and translocation of IRF3, thereby increasing downstream cytokine production. Moreover, the E3 ubiquitin ligase Midline 1 (MID1) facilitated the K48-linked ubiquitination and degradation of NSP9, whereas virus infection inhibited the interaction between MID1 and NSP9, thereby inhibiting NSP9 degradation. Additionally, we identified Lys59 of NSP9 as a critical ubiquitin site involved in the degradation. These findings elucidate a previously unknown mechanism by which a SARS-COV-2 protein promotes cytokine storm and identifies a novel target for COVID-19 treatment.
影响因子：
30.5
作者：
通讯作者：
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