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SESN1 attenuates innate immune response by promoting MAVS autophagic degradation

ABSTRACT: Mitochondrial antiviral signaling protein (MAVS), as a central hub protein in RNA-triggered innate immune response, plays a crucial role in antiviral immunity. The protein stability of MAVS must be strictly regulated to maintain immune homeostasis. However, the exact molecular mechanisms regulating the stability of MAVS remains poorly understood. Here, we reported that SESN1 acts as a critical negative regulator of MAVS by promoting MAVS autophagic degradation to regulate innate immune response. Intriguingly, the expression of SESN1 was dynamic to maintain innate immune homeostasis after RNA virus VSV or IAV PR8 infection. SESN1 mRNA level was decreased at early stage and was rebounded at late stage, which released SESN1-mediated MAVS inhibition to clear virus at early stage and prevent hyper-inflammation at late stage. Moreover, SESN1-deficient mice showed stronger ability against virus infection compared to control mice when challenged with VSV or IAV PR8. Notably, we observed that the expression of SESN1 was markedly downregulated and negatively correlated with cytokines level in patients with influenza. Importantly, the replenishment of SESN1 effectively inhibited cytokine production in the PBMCs of patients with influenza. Mechanistically, SESN1 interacted with MAVS and potentiated MAVS autophagic degradation via SQSTM1. Taken together, these findings revealed a novel regulatory role of SESN1 in innate antiviral immune response by regulating MAVS. Targeting SESN1 might be a potential therapeutic strategy for treating RNA virus infectious disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE299504 | GEO | 2026/09/10

REPOSITORIES: GEO

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Project description:Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.

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SESN1 attenuates innate immune response by promoting MAVS autophagic degradation

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