Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

TRIM34 attenuates colon inflammation and tumorigenesis by sustaining barrier integrity

Abstract

Loss of the colonic inner mucus layer leads to spontaneously severe colitis and colorectal cancer. However, key host factors that may control the generation of the inner mucus layer are rarely reported. Here, we identify a novel function of TRIM34 in goblet cells (GCs) in controlling inner mucus layer generation. Upon DSS treatment, TRIM34 deficiency led to a reduction in Muc2 secretion by GCs and subsequent defects in the inner mucus layer. This outcome rendered TRIM34-deficient mice more susceptible to DSS-induced colitis and colitis-associated colorectal cancer. Mechanistic experiments demonstrated that TRIM34 controlled TLR signaling-induced Nox/Duox-dependent ROS synthesis, thereby promoting the compound exocytosis of Muc2 by colonic GCs that were exposed to bacterial TLR ligands. Clinical analysis revealed that TRIM34 levels in patient samples were correlated with the outcome of ulcerative colitis (UC) and the prognosis of rectal adenocarcinoma. This study indicates that TRIM34 expression in GCs plays an essential role in generating the inner mucus layer and preventing excessive colon inflammation and tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

    CAS  PubMed  Google Scholar 

  2. Danese, S. & Fiocchi, C. Ulcerative Colitis. N. Engl. J. Med. 365, 1713–1725 (2011).

    CAS  PubMed  Google Scholar 

  3. Ng, S. C. et al. Early course of inflammatory bowel disease in a population-based inception cohort study from 8 countries in Asia and Australia. Gastroenterology 150, 86–95 (2016).

    PubMed  Google Scholar 

  4. Molodecky, N. A. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142, 46–54 (2012).

    PubMed  Google Scholar 

  5. Ng, S. C. et al. Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn’s and colitis epidemiology study. Gastroenterology 145, 158–165 (2013).

    PubMed  Google Scholar 

  6. Cohen, R. D. The pharmacoeconomics of biologic therapy for IBD. Nat. Rev. Gastroenterol. Hepatol. 7, 103–109 (2010).

    PubMed  Google Scholar 

  7. de Silva, S., Devlin, S. & Panaccione, R. Optimizing the safety of biologic therapy for IBD. Nat. Rev. Gastroenterol. Hepatol. 7, 93–101 (2010).

    PubMed  Google Scholar 

  8. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Eaden, J. A., Abrams, K. R. & Mayberry, J. F. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48, 526–535 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. von Roon, A. C. et al. The risk of cancer in patients with Crohn’s disease. Dis. Colon Rectum 50, 839–855 (2007).

    Google Scholar 

  11. Beaugerie, L. & Itzkowitz, S. H. Cancers complicating inflammatory bowel disease. N. Engl. J. Med. 372, 1441–1452 (2015).

    CAS  PubMed  Google Scholar 

  12. Weir, H. K. et al. Annual report to the nation on the status of cancer, 1975–2000, featuring the uses of surveillance data for cancer prevention and control. J. Natl Cancer Inst. 95, 1276–1299 (2003).

    PubMed  Google Scholar 

  13. Abraham, C. & Cho, J. H. Inflammatory bowel disease. N. Engl. J. Med. 361, 2066–2078 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Saleh, M. & Elson, C. O. Experimental inflammatory bowel disease: insights into the host-microbiota dialog. Immunity 34, 293–302 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).

    CAS  PubMed  Google Scholar 

  16. Campieri, M. & Gionchetti, P. Bacteria as the cause of ulcerative colitis. Gut 48, 132–135 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sasaki, M. & Klapproth, J. M. The role of bacteria in the pathogenesis of ulcerative colitis. J. Signal Transduct. 2012, 704953 (2012).

    PubMed  PubMed Central  Google Scholar 

  18. Johansson, M. E. V. & Hansson, G. C. Immunological aspects of intestinal mucus and mucins. Nat. Rev. Immunol. 16, 639–649 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kamada, N., Seo, S. U., Chen, G. Y. & Nunez, G. Role of the gut microbiota in immunity and inflammatory disease. Nat. Rev. Immunol. 13, 321–335 (2013).

    CAS  PubMed  Google Scholar 

  20. Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Johansson, M. E., Sjovall, H. & Hansson, G. C. The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 352–361 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Birchenough, G. M., Johansson, M. E., Gustafsson, J. K., Bergstrom, J. H. & Hansson, G. C. New developments in goblet cell mucus secretion and function. Mucosal Immunol. 8, 712–719 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).

    PubMed  Google Scholar 

  24. Velcich, A. et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295, 1726–1729 (2002).

    CAS  PubMed  Google Scholar 

  25. Johansson, M. E. V. et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63, 281–291 (2014).

    CAS  PubMed  Google Scholar 

  26. Kim, J. & Khan, W. Goblet cells and mucins: role in innate defense in enteric infections. Pathogens 2, 55–70 (2013).

    PubMed  PubMed Central  Google Scholar 

  27. McCauley, H. A. & Guasch, G. Three cheers for the goblet cell: maintaining homeostasis in mucosal epithelia. Trends Mol. Med. 21, 492–503 (2015).

    CAS  PubMed  Google Scholar 

  28. Patel, K. K. et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. EMBO J. 32, 3130–3144 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ozato, K., Shin, D. M., Chang, T. H. & Morse, H. C. 3rd. TRIM family proteins and their emerging roles in innate immunity. Nat. Rev. Immunol. 8, 849–860 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kawai, T. & Akira, S. Regulation of innate immune signalling pathways by the tripartite motif (TRIM) family proteins. EMBO Mol. Med. 3, 513–527 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Shi, M. et al. TRIM30 alpha negatively regulates TLR-mediated NF-kappa B activation by targeting TAB2 and TAB3 for degradation. Nat. Immunol. 9, 369–377 (2008).

    CAS  PubMed  Google Scholar 

  33. Wang, Y. et al. TRIM30alpha is a negative-feedback regulator of the intracellular DNA and DNA virus-triggered response by targeting STING. PLoS Pathog. 11, e1005012 (2015).

    PubMed  PubMed Central  Google Scholar 

  34. Yang, B. et al. Novel function of Trim44 promotes an antiviral response by stabilizing VISA. J. Immunol. 190, 3613–3619 (2013).

    CAS  PubMed  Google Scholar 

  35. Wang, Y. et al. TRIM35 negatively regulates TLR7- and TLR9-mediated type I interferon production by targeting IRF7. FEBS Lett. 589, 1322–1330 (2015).

    CAS  PubMed  Google Scholar 

  36. Wirtz, S., Neufert, C., Weigmann, B. & Neurath, M. F. Chemically induced mouse models of intestinal inflammation. Nat. Protoc. 2, 541–546 (2007).

    CAS  PubMed  Google Scholar 

  37. Neufert, C., Becker, C. & Neurath, M. F. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nat. Protoc. 2, 1998–2004 (2007).

    CAS  PubMed  Google Scholar 

  38. Ostanin, D. V. et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G135–G146 (2009).

    CAS  PubMed  Google Scholar 

  39. Zaki, M. H. et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20, 649–660 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Birchenough, G. M. H., Nyström, E. E. L., Johansson, M. E. V. & Hansson, G. C. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science 352, 1535–1542 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Strugala, V., Allen, A., Dettmar, P. W. & Pearson, J. P. Colonic mucin: methods of measuring mucus thickness. Proc. Nutr. Soc. 62, 237–243 (2007).

    Google Scholar 

  42. Lian, Q. et al. Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation. Cell Res. 27, 784–800 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Simmons, A. J. et al. Cytometry-based single-cell analysis of intact epithelial signaling reveals MAPK activation divergent from TNF-alpha-induced apoptosis in vivo. Mol. Syst. Biol. 11, 835 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. Wang, F. et al. Isolation and characterization of intestinal stem cells based on surface marker combinations and colony-formation assay. Gastroenterology 145, 383–395.e381–321 (2013).

    CAS  PubMed  Google Scholar 

  45. Bauernfeind, F. et al. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J. Immunol. 187, 613–617 (2011).

    CAS  PubMed  Google Scholar 

  46. West, A. P. et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472, 476–480 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Bedard, K. & Krause, K. H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87, 245–313 (2007).

    CAS  PubMed  Google Scholar 

  48. Geiszt, M. & Leto, T. L. The Nox family of NAD(P)H oxidases: host defense and beyond. J. Biol. Chem. 279, 51715–51718 (2004).

    CAS  PubMed  Google Scholar 

  49. Lambeth, J. D. & Neish, A. S. Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited. Annu. Rev. Pathol. 9, 119–145 (2014).

    CAS  PubMed  Google Scholar 

  50. Sirokmány, G., Donkó, Á. & Geiszt, M. Nox/Duox family of NADPH oxidases: lessons from knockout mouse models. Trends Pharmacol. Sci. 37, 318–327 (2016).

    PubMed  Google Scholar 

  51. Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gack, M. U. et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446, 916–920 (2007).

    CAS  PubMed  Google Scholar 

  53. Stremlau, M. et al. The cytoplasmic body component TRIM5[alpha] restricts HIV-1 infection in Old World monkeys. Nature 427, 848–853 (2004).

    CAS  PubMed  Google Scholar 

  54. Kamanova, J., Sun, H., Lara-Tejero, M. & Galán, J. E. The salmonella effector protein SopA modulates innate immune responses by targeting TRIM E3 ligase family members. PLoS Pathog. 12, e1005552 (2016).

    PubMed  PubMed Central  Google Scholar 

  55. Sorescu, D. et al. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105, 1429–1435 (2002).

    CAS  PubMed  Google Scholar 

  56. Hassler, M. R. & Egger, G. Epigenomics of cancer—emerging new concepts. Biochimie 94, 2219–2230 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Manea, S.-A., Constantin, A., Manda, G., Sasson, S. & Manea, A. Regulation of Nox enzymes expression in vascular pathophysiology: focusing on transcription factors and epigenetic mechanisms. Redox Biol. 5, 358–366 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Uchil, P. D. et al. TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity. J. Virol. 87, 257–272 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dangsheng Li for critical suggestions. We are grateful to Guomei Lin for breeding the animals and Li Li for animal management. We also acknowledge the individuals involved in technical support at the Core Facility for Cell Biology and the Animal Core Facility. This work was supported by grants from the National Key Research and Development Program of China (2018YFA0507402), the National Natural Science Foundation of China (31230024), the Chinese Academy of Sciences (XDB19000000), and the National Natural Science Foundation of China (81761128009 and 81630016).

Author information

Authors and Affiliations

Authors

Contributions

Q.L., Q.Y., S.Y., and C.Y. designed and performed the experiments and analyzed the data. Y.Z. and X.L. contributed to sample and reagent preparation and discussed the project. W.Z. collected the clinical samples. W.G. assisted with the intravenous injections and reagents. X.Z. and W.F. provided suggestions and reagents and discussed the data. L.M. prepared cell lines and provided reagents. Q.L. wrote the paper. B.S., J.L., J.L., and Y.Z. supervised the project and revised the paper.

Corresponding authors

Correspondence to Yaguang Zhang, Jie Liu, Jinsong Li or Bing Sun.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lian, Q., Yan, S., Yin, Q. et al. TRIM34 attenuates colon inflammation and tumorigenesis by sustaining barrier integrity. Cell Mol Immunol 18, 350–362 (2021). https://doi.org/10.1038/s41423-020-0366-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-0366-2

Keywords

This article is cited by

Search

Quick links