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

作　　者：Lin-Wen Zeng Lu Feng Rui Liu Heng Lin Hong-Bing Shu Shu Li 

机构地区：[1]Department of Infectious Diseases,Zhongnan Hospital of Wuhan University,Medical Research Institute,Frontier Science Center for Immunology and Metabolism,Research Unit of Innate Immune and Inflammatory Diseases(2019RU063),Chinese Academy of Medical Sciences,Wuhan University,Wuhan,430071,China

出　　处：《Cellular & Molecular Immunology》2022年第10期1117-1129,共13页中国免疫学杂志（英文版）

基　　金：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);the Fundamental Research Funds for the Central Universities.

摘　　要：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 receptorαchain(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-5Rαand 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-5Rαfor degradation and negatively regulating allergic airway inflammation.

关 键 词：MARCH2/3 IL-5Rα POLYUBIQUITINATION EOSINOPHIL Airway inflammation 

分 类 号：R562.2[医药卫生—呼吸系统]