Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity

Haibo Zhang, Keke Xue, Wen Li, Xinyi Yang, Yusen Gou, Xiao Su, Feng Qian () and Lei Sun ()
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Haibo Zhang: School of Pharmaceutical Sciences, Shanghai Jiao Tong University
Keke Xue: School of Pharmaceutical Sciences, Shanghai Jiao Tong University
Wen Li: School of Pharmaceutical Sciences, Shanghai Jiao Tong University
Xinyi Yang: School of Pharmaceutical Sciences, Shanghai Jiao Tong University
Yusen Gou: 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
Lei Sun: School of Pharmaceutical Sciences, Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44168-0

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