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
  • 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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