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.
Highlights
Interleukin-3 (IL-3) is a hematopoietic growth factor that is mainly secreted by activated T-cells
We have previously demonstrated that the two membrane- March[2] down-regulates Il-3rα level as well as associated E3 ubiquitin ligases MARCH3 and MARCH8 negatively negatively regulates Il-3-triggered signaling in mouse bone marrow-derived macrophages (BMDMs)
We co-transfected IL-3 receptor α (IL-3Rα) with downregulates IL-3Rα, we firstly examined whether MARCH3 is each of the 11 membrane-associated RING-CH-type finger (MARCH) family members in human embryonic associated with IL-3Rα
Summary
Interleukin-3 (IL-3) is a hematopoietic growth factor that is mainly secreted by activated T-cells. IL-3 serves as a growth factor for leukemic colonies with an elevated IL-3 receptor α-chain (IL-3Rα, CD123) such as acute myeloid leukemia, chronic myelogenous leukemia or plasmacytoid dendritic cell neoplasm.[2,3] It has been demonstrated that IL-3 amplifies acute inflammation in murine sepsis, and elevated plasma levels of IL-3 are associated with high mortality in human sepsis.[4] Recently, it has been shown that the astrocyte-sourced IL3 programs microglia to ameliorate the pathology of Alzheimer’s disease in human and mice.[5]. In addition to the JAK/STAT pathway, IL-3 activates
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