2. Academic Validation
  3. Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity

Cullin5 drives experimental asthma exacerbations by modulating alveolar macrophage antiviral immunity

  • Nat Commun. 2024 Jan 4;15(1):252. doi: 10.1038/s41467-023-44168-0.
Haibo Zhang 1 2 3,  Keke Xue 1 2 3,  Wen Li 1 2 3,  Xinyi Yang 1 2 3,  Yusen Gou 1 2 3,  Xiao Su 4,  Feng Qian 5 6 7,  Lei Sun 8 9 10
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China.
  • 2 National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China.
  • 3 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China.
  • 4 Unit of Respiratory Infection and Immunity, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 200031, Shanghai, P.R. China.
  • 5 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China. [email protected].
  • 6 National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China. [email protected].
  • 7 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China. [email protected].
  • 8 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China. [email protected].
  • 9 National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China. [email protected].
  • 10 Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, 200240, Shanghai, P. R. China. [email protected].
PMID: 38177117 DOI: 10.1038/s41467-023-44168-0
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.

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