ウイルス感染初期の抗ウイルス応答選択機構の解析

病毒感染早期抗病毒反应选择机制分析

• 批准号: 21J14073
• 负责人: 趙 東儀
• 金额: $ 0.96万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-04-28 至 2023-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21J14073/
• 关键词: Type I IFN; Apoptosis; MAVS; ASK1

Host cells activate the first line of defense mechanisms, such as apoptosis or induction of type I interferon (IFN), to prevent virus replication and proliferation upon virus infection. RIG-I-like receptors (RLRs) recognize single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA) of viruses, and bind with Mitochondrial antiviral signaling (MAVS) to induce these defense responses. Among the MAP3Ks mediating the innate immune response to viruses via MAVS, ASK1 is particularly important. Previous studies have discovered that Apoptosis Signal Regulating Kinase 1 (ASK1) promotes the expression of type I IFN in response to virus infection. However, it was unclear how ASK1 controls type I IFN production.Our research revealed that ASK1 promotes the phosphorylation of MAVS. In MEFs expressing a MAVS phosphorylation-defective mutant, the production of type I IFN was suppressed and the replication of Sendai virus was promoted upon virus infection. These results suggest that the phosphorylation of MAVS mediated by ASK1 is necessary for protection against virus infection.In summary, our research suggests that the phosphorylation of MAVS mediated by ASK1 is necessary for the protection of host cells against virus infection.

宿主细胞激活第一道防线机制，如细胞凋亡或诱导I型干扰素（IFN），以防止病毒感染后的病毒复制和增殖。RIG-I样受体（RIG-I-like receptors，RLR）识别病毒的单链RNA（single-stranded RNA，ssRNA）或双链RNA（double-stranded RNA，dsRNA），并与线粒体抗病毒信号（Mitochondrial antiviral signaling，MAVS）结合，诱导病毒的防御反应。在通过MAVS介导对病毒的先天免疫应答的MAP 3 K中，ASK 1特别重要。以往的研究发现，细胞凋亡信号调节激酶1（Apoptosis Signal Regulating Kinase 1，ASK 1）在病毒感染后促进I型干扰素的表达。然而，目前还不清楚ASK 1是如何控制I型IFN的产生的，我们的研究表明，ASK 1促进MAVS的磷酸化。在表达MAVS磷酸化缺陷突变体的MEF中，病毒感染后I型IFN的产生受到抑制，仙台病毒的复制得到促进。这些结果表明，由ASK 1介导的MAVS磷酸化是保护宿主细胞免受病毒感染所必需的。总之，我们的研究表明，由ASK 1介导的MAVS磷酸化是保护宿主细胞免受病毒感染所必需的。