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Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity

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  • Haibo Zhang

    (School of Pharmaceutical Sciences, Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University)

  • Keke Xue

    (School of Pharmaceutical Sciences, Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University)

  • Wen Li

    (School of Pharmaceutical Sciences, Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University)

  • Xinyi Yang

    (School of Pharmaceutical Sciences, Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University)

  • Yusen Gou

    (School of Pharmaceutical Sciences, Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University)

  • Xiao Su

    (Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences)

  • Feng Qian

    (School of Pharmaceutical Sciences, Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University)

  • Lei Sun

    (School of Pharmaceutical Sciences, Shanghai Jiao Tong University
    Shanghai Jiao Tong University
    Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University)

Abstract

Asthma exacerbations caused by respiratory viral infections are a serious global health problem. Impaired antiviral immunity is thought to contribute to the pathogenesis, but the underlying mechanisms remain understudied. Here using mouse models we find that Cullin5 (CUL5), a key component of Cullin-RING E3 ubiquitin ligase 5, is upregulated and associated with increased neutrophil count and influenza-induced exacerbations of house dust mite-induced asthma. By contrast, CUL5 deficiency mitigates neutrophilic lung inflammation and asthma exacerbations by augmenting IFN-β production. Mechanistically, following thymic stromal lymphopoietin stimulation, CUL5 interacts with O-GlcNAc transferase (OGT) and induces Lys48-linked polyubiquitination of OGT, blocking the effect of OGT on mitochondrial antiviral-signaling protein O-GlcNAcylation and RIG-I signaling activation. Our results thus suggest that, in mouse models, pre-existing allergic injury induces CUL5 expression, impairing antiviral immunity and promoting neutrophilic inflammation for asthma exacerbations. Targeting of the CUL5/IFN-β signaling axis may thereby serve as a possible therapy for treating asthma exacerbations.

Suggested Citation

  • Haibo Zhang & Keke Xue & Wen Li & Xinyi Yang & Yusen Gou & Xiao Su & Feng Qian & Lei Sun, 2024. "Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44168-0
    DOI: 10.1038/s41467-023-44168-0
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