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