SESN1 is a negative regulator of MAVS and dynamically expressed during RNA viral infection

• 成果类型: Article
• 署名作者: Liu, Qianghui; Chen, Peiran; He, Chunyan; Qiu, Zuocheng; Zhang, Yubo; Wang, Jia; Xu, Lingxiao; Xu, Yong; Pan, Mingyu
• 署名单位: Nanjing Medical University; City University of Hong Kong; Jinan University; Jinan University; Jinan University; Nanjing Medical University; Nanjing Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2621443123
• 发表日期: 2026-09-01
• 页码: e2621443123
• 关键词: autophagy; innate immunity; mavs; SESN1; rna virus; degradation; autophagy; responses; immunity

摘要

RNA viruses, major pathogens of humans and animals, are responsible for numerous inflammatory diseases. Commonly, mild RNA virus infection fails to trigger inflammatory diseases due to host immune homeostasis. However, severe RNA virus infection destroys immune homeostasis and causes hyperinflammation. The detail mechanism is still unclear. Here, we reported that SESN1 acts as a critical negative regulator of mitochondrial antiviral signaling protein (MAVS), a central hub protein in RNA-triggered innate immune response, by potentiating MAVS autophagic degradation to repress innate immune response. Upon low dose RNA virus infection, SESN1 level was decreased at infection early stage and was rebounded at late stage, which restrained SESN1-mediated MAVS degradation to clear virus at early stage and enhanced MAVS degradation to prevent excessive cytokines production at late stage. Whereas, SESN1 level was continuously impaired after high dose RNA virus infection, which caused robust cytokines production. Notably, we observed that the expression of SESN1 was markedly downregulated and negatively correlated with cytokine levels in patients with severe influenza. Replenishment of SESN1 effectively inhibited cytokines production in the Human Primary Bronchial/Tracheal Epithelial Cells infected with Influenza A virus PR8 and peripheral blood mononuclear cells of patients with severe influenza. Mechanistically, SESN1 interacted with MAVS and enhanced MAVS autophagic degradation via SQSTM1. Together, these findings revealed SESN1 was an important factor to regulate host innate immune response.