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The membrane-associated ubiquitin ligases MARCH2 and MARCH3 target IL-5 receptor alpha to negatively regulate eosinophilic airway inflammation

Abstract

Interleukin 5 (IL-5) plays crucial roles in type 2-high asthma by mediating eosinophil maturation, activation, chemotaxis and survival. Inhibition of IL-5 signaling is considered a strategy for asthma treatment. Here, we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling. MARCH2 and MARCH3 associate with the IL-5 receptor α chain (IL-5Rα) and mediate its K27-linked polyubiquitination at K379 and K383, respectively, and its subsequent lysosomal degradation. Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rα and enhances IL-5-induced signaling, whereas double knockout of MARCH2/3 has a more dramatic effect. March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice. Double knockout of March2/3 aggravates ovalbumin (OVA)-induced eosinophilia and causes increased inflammatory cell infiltration, peribronchial mucus secretion and production of Th2 cytokines. Neutralization of Il-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency. These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rα for degradation and negatively regulating allergic airway inflammation.

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Data availability

All data needed to evaluate the conclusions in the paper are presented in the paper. The materials described in the study are either commercially available or available upon request from the corresponding author.

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Acknowledgements

We thank Deng Gao, Xuemei Yi, Mi Li, Ru Zang, Chen Li, and Li Zhong for technical help and academic discussions and sincerely appreciate all the staff at the core facility of the Medical Research Institute at Wuhan University for their technical support. This work was supported by grants from the National Natural Science Foundation of China (32188101, 31830024 and 32070775), the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-071) and the Fundamental Research Funds for the Central Universities.

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SL, H-BS, and L-WZ conceived and designed the study. L-WZ, LF, RL, and HL performed the experiments. SL, L-WZ, and H-BS analyzed the data and wrote the manuscript.

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Correspondence to Shu Li.

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Zeng, LW., Feng, L., Liu, R. et al. The membrane-associated ubiquitin ligases MARCH2 and MARCH3 target IL-5 receptor alpha to negatively regulate eosinophilic airway inflammation. Cell Mol Immunol 19, 1117–1129 (2022). https://doi.org/10.1038/s41423-022-00907-9

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  • DOI: https://doi.org/10.1038/s41423-022-00907-9

Keywords

  • MARCH2/3
  • IL-5Rα
  • Polyubiquitination
  • Eosinophil
  • Airway inflammation

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