biostudies-literatureLin HNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)2648-2659https://www.ebi.ac.uk/biostudies/studies/S-EPMC8632971biostudies-literatureUnknown18(12)The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis (IAC). How this axis is regulated to modulate IAC remains unknown. Here, we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6, as well as another IL-6 subfamily member, Oncostatin M (OSM). MARCH3 is associated with the IL-6 receptor α-chain (IL-6Rα) and its coreceptor gp130. Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rα at K401 and gp130 at K849 following IL-6 stimulation, leading to their translocation to and degradation in lysosomes. MARCH3 deficiency increases IL-6- and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types. MARCH3 deficiency enhCellular & molecular immunologyThe membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis.PMC863297131830024Zeng LWFeng LCui KSLi SZhang LXSun YHLin HXu WHShu HBGao DfalseThe membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis.The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis (IAC). How this axis is regulated to modulate IAC remains unknown. Here, we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6, as well as another IL-6 subfamily member, Oncostatin M (OSM). MARCH3 is associated with the IL-6 receptor α-chain (IL-6Rα) and its coreceptor gp130. Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rα at K401 and gp130 at K849 following IL-6 stimulation, leading to their translocation to and degradation in lysosomes. MARCH3 deficiency increases IL-6- and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types. MARCH3 deficiency enh2021-01-01T00:00:00Z2021 Dec2025-04-25T20:50:59.866Z2025-04-06T08:33:41.591ZS-EPMC86329713478573210.1038/s41423-021-00799-1