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MARCH3 negatively regulates IL-3-triggered inflammatory response by mediating K48-linked polyubiquitination and degradation of IL-3Rα
- Source :
- Signal Transduction and Targeted Therapy, Vol 7, Iss 1, Pp 1-12 (2022)
- Publication Year :
- 2022
- Publisher :
- Nature Publishing Group, 2022.
-
Abstract
- Abstract 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.
- Subjects :
- Medicine
Biology (General)
QH301-705.5
Subjects
Details
- Language :
- English
- ISSN :
- 20593635
- Volume :
- 7
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Signal Transduction and Targeted Therapy
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.66a388dcff41cda067d8c04f442f3a
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41392-021-00834-7