MARCH3 negatively regulates IL-3-triggered inflammatory response by mediating K48-linked polyubiquitination and degradation of IL-3Rα  

作　　者：Lu Feng Chen Li Lin-Wen Zeng Deng Gao Yu-Hao Sun Li Zhong 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,Chinese Academy of Medical Sciences,Wuhan University,430071 Wuhan,China

出　　处：《Signal Transduction and Targeted Therapy》2022年第2期519-530,共12页信号转导与靶向治疗（英文）

基　　金：This work was supported by grants from the State Key R&D Program of China(2017YFA0505800);the National Natural Science Foundation of China(31830024 and 32070775);the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).

摘　　要：Interleukin-3(IL-3)is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis.IL-3 binds to IL-3 receptorα(IL-3Rα),which is then associated with IL-3Rβto initiate signaling.How IL-3-triggered physiological and pathological effects are regulated at the receptor level is unclear.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates IL-3-triggered signaling.MARCH3 is associated with IL-3Rα,mediates its K48-linked polyubiquitination at K377 and promotes its proteasomal degradation.MARCH3-deficiency promotes IL-3-triggered transcription of downstream effector genes and IL-3-induced expansion of myeloid cells.In the cecal ligation and puncture(CLP)model of sepsis,MARCH3-deficiency aggravates IL-3-ampified expression of inflammatory cytokines,organ damage and inflammatory death.Our findings suggest that regulation of IL-3Rαby MARCH3 plays an important role in IL-3-triggered physiological functions and inflammatory diseases.

关 键 词：INFLAMMATORY UBIQUITIN DAMAGE MARCH 

分 类 号：R3[医药卫生—基础医学]