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

Lu Feng, Chen Li, Lin-Wen Zeng, Deng Gao, Yu-Hao Sun, Li Zhong, Heng Lin, Hong-Bing Shu, Shu Li

Signal transduction and targeted therapy 2022 Jan 24

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Interleukin-3 (IL-3) is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis. IL-3 binds to IL-3 receptor α (IL-3Rα), which is then associated with IL-3Rβ to 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-3Rα by MARCH3 plays an important role in IL-3-triggered physiological functions and inflammatory diseases. © 2021. The Author(s).

Citation

Lu Feng, Chen Li, Lin-Wen Zeng, Deng Gao, Yu-Hao Sun, Li Zhong, Heng Lin, Hong-Bing Shu, Shu Li. MARCH3 negatively regulates IL-3-triggered inflammatory response by mediating K48-linked polyubiquitination and degradation of IL-3Rα. Signal transduction and targeted therapy. 2022 Jan 24;7(1):21