RTN3 inhibits RIG-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination.
RTN3 inhibits RIG-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination.
复制标题
RTN3 通过损害 TRIM25 介导的 K63 连接的多聚泛素化来抑制 RIG-I 介导的抗病毒反应。
DOI：
10.7554/elife.68958
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发表时间：
2021-07-27
期刊：
影响因子：
7.7
通讯作者：
Kuang E
中科院分区：
文献类型：
--
作者：
Yang Z;Wang J;He B;Zhang X;Li X;Kuang E
在病毒RNA识别后，RIG-I信号体持续产生IFN和细胞因子，导致中性粒细胞募集和炎症。因此，减弱过度的免疫和炎症反应对于恢复免疫稳态和防止不必要的损伤至关重要，但很少有解决介质已被确定。在本研究中，我们证明了RTN 3在RNA病毒感染期间强烈上调，并作为炎症消退调节剂。增加的RTN 3聚集在内质网上并与TRIM 25和RIG-1相互作用，随后损害K63连接的多聚泛素化，并导致IRF 3和NF-κB抑制。Rtn 3过表达的小鼠在VSV攻击时表现出明显的炎症消退现象，Rtn 3过表达的小鼠表现出显著的中性粒细胞数量减少和炎性细胞浸润，伴随着肝脏组织水肿减轻和肺泡上皮变薄。总之，我们的研究结果将RTN 3确定为免疫和炎症反应的保守负调节因子，并提供了对维持免疫和炎症稳态的负反馈的见解。
Upon viral RNA recognition, the RIG-I signalosome continuously generates IFNs and cytokines, leading to neutrophil recruitment and inflammation. Thus, attenuation of excessive immune and inflammatory responses is crucial to restore immune homeostasis and prevent unwarranted damage, yet few resolving mediators have been identified. In the present study, we demonstrated that RTN3 is strongly upregulated during RNA viral infection and acts as an inflammation-resolving regulator. Increased RTN3 aggregates on the endoplasmic reticulum and interacts with both TRIM25 and RIG-I, subsequently impairing K63-linked polyubiquitination and resulting in both IRF3 and NF-κB inhibition. Rtn3 overexpression in mice causes an obvious inflammation resolving phenomenon when challenged with VSV, Rtn3-overexpressing mice display significantly decreased neutrophil numbers and inflammatory cell infiltration, which is accompanied by reduced tissue edema in the liver and thinner alveolar interstitium. Taken together, our findings identify RTN3 as a conserved negative regulator of immune and inflammatory responses and provide insights into the negative feedback that maintains immune and inflammatory homeostasis.