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

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.