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Ubiquitin-specific protease 47 regulates intestinal inflammation through deubiquitination of TRAF6 in epithelial cells

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Abstract

Deubiquitinates (DUBs) alter the stabilities, localizations or activities of substrates by removing their ubiquitin conjugates, which are closely related to the development of inflammatory response. Here, we show that ubiquitin-specific protease 47 (USP47) prevents inflammation development in inflammatory bowel disease (IBD). Compared with wild-type mice, Usp47 knockout mice are more susceptible to dextran sodium sulfate (DSS)-induced acute and chronic colitis with higher inflammatory cytokines expression and severe intestinal tissue damage. Chimeric mouse experiments suggest that non-hematopoietic cells mainly contribute to the phenotype. And, DSS-induced colitis of the Usp47 knockout mice depends on commensal bacteria. Mechanistically, down-regulation of USP47 aggravates the activation of NF-κB signaling pathway by increasing the K63-linked poly-ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) in intestinal epithelial cells. Furthermore, the expression of USP47, negatively correlated with the degree of inflammation, is lower at colonic inflammatory lesions than that non-inflammatory sites from the intestine from ulcerative colitis (UC) and Crohn’s disease (CD) patients. These data, taken together, indicate that USP47 regulates intestinal inflammation through de-ubiquitination of K63-linked poly-ubiquitination TRAF6 in intestinal epithelial cells.

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References

  • Artis, D. (2008). Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol 8, 411–420.

    Article  CAS  Google Scholar 

  • Ashton-Beaucage, D., Lemieux, C., Udell, C.M., Sahmi, M., Rochette, S., and Therrien, M. (2016). The deubiquitinase USP47 stabilizes MAPK by counteracting the function of the N-end rule ligase POE/UBR4 in Drosophila. PLoS Biol 14, e1002539.

    Article  Google Scholar 

  • Burgueño, J.F., and Abreu, M.T. (2020). Epithelial Toll-like receptors and their role in gut homeostasis and disease. Nat Rev Gastroenterol Hepatol 17, 263–278.

    Article  Google Scholar 

  • Chang, J.T. (2020). Pathophysiology of inflammatory bowel diseases. N Engl J Med 383, 2652–2664.

    Article  CAS  Google Scholar 

  • Cho, J., Park, J., Shin, S.C., Jang, M., Kim, J.H., Kim, E.E.K., and Song, E. J. (2020). USP47 promotes tumorigenesis by negative regulation of p53 through deubiquitinating ribosomal protein S2. Cancers 12, 1137.

    Article  CAS  Google Scholar 

  • Choi, B.J., Park, S.A., Lee, S.Y., Cha, Y.N., and Surh, Y.J. (2017). Hypoxia induces epithelial-mesenchymal transition in colorectal cancer cells through ubiquitin-specific protease 47-mediated stabilization of Snail: a potential role of Sox9. Sci Rep 7, 15918.

    Article  Google Scholar 

  • Daubeuf, S., Singh, D., Tan, Y., Liu, H., Federoff, H.J., Bowers, W.J., and Tolba, K. (2009). HSV ICP0 recruits USP7 to modulate TLR-mediated innate response. Blood 113, 3264–3275.

    Article  CAS  Google Scholar 

  • Ding, S., Yan, W., Fang, J., Jiang, H., and Liu, G. (2021). Potential role of Lactobacillus plantarum in colitis induced by dextran sulfate sodium through altering gut microbiota and host metabolism in murine model. Sci China Life Sci 64, 1906–1916.

    Article  CAS  Google Scholar 

  • Fu, T.M., Shen, C., Li, Q., Zhang, P., and Wu, H. (2018). Mechanism of ubiquitin transfer promoted by TRAF6. Proc Natl Acad Sci USA 115, 1783–1788.

    Article  CAS  Google Scholar 

  • Greten, F.R., Eckmann, L., Greten, T.F., Park, J.M., Li, Z.W., Egan, L.J., Kagnoff, M.F., and Karin, M. (2004). IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296.

    Article  CAS  Google Scholar 

  • Guma, M., Stepniak, D., Shaked, H., Spehlmann, M.E., Shenouda, S., Cheroutre, H., Vicente-Suarez, I., Eckmann, L., Kagnoff, M.F., and Karin, M. (2011). Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation. J Exp Med 208, 1889–1900.

    Article  CAS  Google Scholar 

  • Hou, X., Xia, J., Feng, Y., Cui, L., Yang, Y., Yang, P., and Xu, X. (2021). USP47-mediated deubiquitination and stabilization of TCEA3 attenuates pyroptosis and apoptosis of colorectal cancer cells induced by chemotherapeutic doxorubicin. Front Pharmacol 12, 713322.

    Article  CAS  Google Scholar 

  • Kawai, T., and Akira, S. (2007). TLR signaling. Semin Immunol 19, 24–32.

    Article  CAS  Google Scholar 

  • Lamothe, B., Besse, A., Campos, A.D., Webster, W.K., Wu, H., and Darnay, B.G. (2007). Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of IκB kinase activation. J Biol Chem 282, 4102–4112.

    Article  CAS  Google Scholar 

  • Lasry, A., Zinger, A., and Ben-Neriah, Y. (2016). Inflammatory networks underlying colorectal cancer. Nat Immunol 17, 230–240.

    Article  CAS  Google Scholar 

  • Lei, H., Xu, H.Z., Shan, H.Z., Liu, M., Lu, Y., Fang, Z.X., Jin, J., Jing, B., Xiao, X.H., Gao, S.M., et al. (2021). Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia. Nat Commun 12, 51.

    Article  CAS  Google Scholar 

  • Liu, C., Qian, W., Qian, Y., Giltiay, N.V., Lu, Y., Swaidani, S., Misra, S., Deng, L., Chen, Z.J., and Li, X. (2009). Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci Signal 2.

  • Lomaga, M.A., Yeh, W.C., Sarosi, I., Duncan, G.S., Furlonger, C., Ho, A., Morony, S., Capparelli, C., Van, G., Kaufman, S., et al. (1999). TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13, 1015–1024.

    Article  CAS  Google Scholar 

  • Lu, Y., Li, X., Liu, S., Zhang, Y., and Zhang, D. (2018). Toll-like receptors and inflammatory bowel disease. Front Immunol 9, 72.

    Article  Google Scholar 

  • McGovern, D.P.B., Gardet, A., Törkvist, L., Goyette, P., Essers, J., Taylor, K.D., Neale, B.M., Ong, R.T.H., Lagacé, C., Li, C., et al. (2010). Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42, 332–337.

    Article  CAS  Google Scholar 

  • Mehandru, S., and Colombel, J.F. (2021). The intestinal barrier, an arbitrator turned provocateur in IBD. Nat Rev Gastroenterol Hepatol 18, 83–84.

    Article  Google Scholar 

  • Moallemian, R., Rehman, A.U., Zhao, N., Wang, H., Chen, H., Lin, G., Ma, X., and Yu, J. (2020). Immunoproteasome inhibitor DPLG3 attenuates experimental colitis by restraining NF-κB activation. Biochem Pharmacol 177, 113964.

    Article  CAS  Google Scholar 

  • Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M., Nikolaev, A., Neufert, C., Madison, B., et al. (2007). Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561.

    Article  CAS  Google Scholar 

  • Okumura, R., and Takeda, K. (2017). Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Exp Mol Med 49, e338.

    Article  CAS  Google Scholar 

  • Okumura, R., and Takeda, K. (2018). Maintenance of intestinal homeostasis by mucosal barriers. Inflamm Regen 38, 5.

    Article  Google Scholar 

  • Palazón-Riquelme, P., Worboys, J.D., Green, J., Valera, A., Martín-Sánchez, F., Pellegrini, C., Brough, D., and López-Castejón, G. (2018). USP7 and USP47 deubiquitinases regulate NLRP3 inflammasome activation. EMBO Rep 19.

  • Pan, B., Yang, Y., Li, J., Wang, Y., Fang, C., Yu, F.X., and Xu, Y. (2020). USP47-mediated deubiquitination and stabilization of YAP contributes to the progression of colorectal cancer. Protein Cell 11, 138–143.

    Article  Google Scholar 

  • Parsons, J.L., Dianova, I.I., Khoronenkova, S.V., Edelmann, M.J., Kessler, B.M., and Dianov, G.L. (2011). USP47 is a deubiquitylating enzyme that regulates base excision repair by controlling steady-state levels of DNA polymerase β. Mol Cell 41, 609–615.

    Article  CAS  Google Scholar 

  • Peschiaroli, A., Skaar, J.R., Pagano, M., and Melino, G. (2010). The ubiquitin-specific protease USP47 is a novel β-TRCP interactor regulating cell survival. Oncogene 29, 1384–1393.

    Article  CAS  Google Scholar 

  • Rakoff-Nahoum, S., Hao, L., and Medzhitov, R. (2006). Role of Toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329.

    Article  CAS  Google Scholar 

  • Sako-Kubota, K., Tanaka, N., Nagae, S., Meng, W., and Takeichi, M. (2014). Minus end-directed motor KIFC3 suppresses E-cadherin degradation by recruiting USP47 to adherens junctions. Mol Biol Cell 25, 3851–3860.

    Article  Google Scholar 

  • Tran, A.T., Rahim, M.N., Ranadheera, C., Kroeker, A., Cortens, J.P., Opanubi, K.J., Wilkins, J.A., and Coombs, K.M. (2013). Knockdown of specific host factors protects against influenza virus-induced cell death. Cell Death Dis 4, e769.

    Article  CAS  Google Scholar 

  • Vlantis, K., Polykratis, A., Welz, P.S., van Loo, G., Pasparakis, M., and Wullaert, A. (2016). TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice. Gut 65, 935–943.

    Article  CAS  Google Scholar 

  • Vlantis, K., Wullaert, A., Sasaki, Y., Schmidt-Supprian, M., Rajewsky, K., Roskams, T., and Pasparakis, M. (2011). Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. J Clin Invest 121, 2781–2793.

    Article  CAS  Google Scholar 

  • Walsh, M.C., Lee, J.E., and Choi, Y. (2015). Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev 266, 72–92.

    Article  CAS  Google Scholar 

  • Wu, N., Chen, D., Sun, H., Tan, J., Zhang, Y., Zhang, T., Han, Y., Liu, H., Ouyang, X., Yang, X.D., et al. (2021). MAP3K2 augments Th1 cell differentiation via IL-18 to promote T cell-mediated colitis. Sci China Life Sci 64, 389–403.

    Article  CAS  Google Scholar 

  • Yu, L., Dong, L., Wang, Y., Liu, L., Long, H., Li, H., Li, J., Yang, X., Liu, Z., Duan, G., et al. (2019). Reversible regulation of SATB1 ubiquitination by USP47 and SMURF2 mediates colon cancer cell proliferation and tumor progression. Cancer Lett 448, 40–51.

    Article  CAS  Google Scholar 

  • Zhang, B., Yin, Y., Hu, Y., Zhang, J., Bian, Z., Song, M., Hua, D., and Huang, Z. (2015). MicroRNA-204-5p inhibits gastric cancer cell proliferation by downregulating USP47 and RAB22A. Med Oncol 32, 331.

    Article  Google Scholar 

  • Zhao, Z.J., Xiang, J.Y., Liu, L., Huang, X.L., and Gan, H.T. (2012). Parthenolide, an inhibitor of the nuclear factor-κB pathway, ameliorates dextran sulfate sodium-induced colitis in mice. Int Immunopharmacol 12, 169–174.

    Article  CAS  Google Scholar 

  • Zhen, Y., and Zhang, H. (2019). NLRP3 inflammasome and inflammatory bowel disease. Front Immunol 10, 276.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the National Key Research and Development Program of China (2017YFA0505202), the National Natural Science Foundation of China (81700475) and the Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases and the State Key Laboratory of Oncogenes and Related Genes (KF2107).

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  1. Contributed equally to this work

Authors and Affiliations

  1. Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Hu Lei, Li Yang, Hanzhang Xu, Xiangyun Li, Meng Liu & Yingli Wu

  2. Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Zhengting Wang

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  1. Hu Lei
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Correspondence to Hu Lei or Yingli Wu.

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Compliance and ethics The author(s) declare that they have no conflict of interest. All animal experiments were performed according to the guidelines for the use and care of laboratory animals as provided by Shanghai Jiao Tong University School of Medicine Institutional Animal Care and Use Committees (IACUC). All procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation of Shanghai Jiao Tong University School of Medicine. Informed consent was obtained from all patients for being included in the study.

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Lei, H., Yang, L., Xu, H. et al. Ubiquitin-specific protease 47 regulates intestinal inflammation through deubiquitination of TRAF6 in epithelial cells. Sci. China Life Sci. 65, 1624–1635 (2022). https://doi.org/10.1007/s11427-021-2040-8

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