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The membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis

Cellular & Molecular Immunology volume 18, pages 2648–2659 (2021)Cite this article

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Abstract

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 enhances dextran sulfate sodium (DSS)-induced STAT3 activation, increases the expression of inflammatory cytokines, and exacerbates colitis, as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer in mice. In addition, MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types. Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation, inflammation, and inflammation-associated carcinogenesis.

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Acknowledgements

We thank members of our laboratory for technical help and discussions. This work was supported by grants from the National Key R&D Program of China (2017YFA0505800), the National Natural Science Foundation of China (31630045, 31830024, 31900556, and 32070775), the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-071), the National Postdoctoral Program for Innovative Talents (BX20190255) and the China Postdoctoral Science Foundation (2019M662706).

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Authors and Affiliations

  1. Department of Infectious Diseases, Zhongnan Hospital of Wuhan University; Medical Research Institute; Frontier Science Center for Immunology and Metabolism; Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences; Wuhan University, Wuhan, 430071, China

    Heng Lin, Lu Feng, Lin-Wen Zeng, Deng Gao, Long-Xiang Zhang, Wen-Hua Xu, Yu-Hao Sun, Hong-Bing Shu & Shu Li

  2. Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, 214062, Jiangsu, China

    Kai-Sa Cui

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  1. Heng Lin
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Contributions

H-BS, SL, and HL conceived and designed the study. HL, LF, DG, L-XZ, W-HX, L-WZ, and Y-HS performed the experiments. H-BS, HL, and SL analyzed the data. K-SC performed bioinformatics data analysis and visualization. H-BS, SL, and HL wrote the manuscript.

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Correspondence to Hong-Bing Shu or Shu Li.

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Lin, H., Feng, L., Cui, KS. et al. The membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis. Cell Mol Immunol 18, 2648–2659 (2021). https://doi.org/10.1038/s41423-021-00799-1

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