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The ulcerative colitis-associated gene FUT8 regulates the quantity and quality of secreted mucins.

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Title: The ulcerative colitis-associated gene FUT8 regulates the quantity and quality of secreted mucins.
Authors: Cantero-Recasens, Gerard1,2 gerard.cantero@vhir.org, Burballa, Carla1,2, Yuki Ohkawa3, Tomohiko Fukuda4, Yoichiro Harada3, Curwin, Amy J.1, Brouwers, Nathalie1, Thun, Gian A.5, Jianguo Gu4, Gut, Ivo5, Naoyuki Taniguchi3, Malhotra, Vivek1,6,7 vivek.malhotra@crg.eu
Source: Proceedings of the National Academy of Sciences of the United States of America. 10/25/2022, Vol. 119 Issue 43, p1-10. 22p.
Subjects: Mucins, Ulcerative colitis, Alimentary canal, Shearing force, Cell membranes
Abstract: Mucins are the main macrocomponents of the mucus layer that protects the digestive tract from pathogens. Fucosylation of mucins increases mucus viscoelasticity and its resistance to shear stress. These properties are altered in patients with ulcerative colitis (UC), which is marked by a chronic inflammation of the distal part of the colon. Here, we show that levels of Fucosyltransferase 8 (FUT8) and specific mucins are increased in the distal inflamed colon of UC patients. Recapitulating this FUT8 overexpression in mucin-producing HT29-18N2 colonic cell line increases delivery of MUC1 to the plasma membrane and extracellular release of MUC2 and MUC5AC. Mucins secreted by FUT8 overexpressing cells are more resistant to removal from the cell surface than mucins secreted by FUT8-depleted cells (FUT8 KD). FUT8 KD causes intracellular accumulation of MUC1 and alters the ratio of secreted MUC2 to MUC5AC. These data fit well with the Fut82/2 mice phenotype, which are protected from UC. Fut82/2 mice exhibit a thinner proximal colon mucus layer with an altered ratio of neutral to acidic mucins. Together, our data reveal that FUT8 modifies the biophysical properties of mucus by controlling levels of cell surface MUC1 and quantity and quality of secreted MUC2 and MUC5AC. We suggest that these changes in mucus viscoelasticity likely facilitate bacterial-epithelial interactions leading to inflammation and UC progression. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: The ulcerative colitis-associated gene FUT8 regulates the quantity and quality of secreted mucins.
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  Data: <searchLink fieldCode="AR" term="%22Cantero-Recasens%2C+Gerard%22">Cantero-Recasens, Gerard</searchLink><relatesTo>1,2</relatesTo><i> gerard.cantero@vhir.org</i><br /><searchLink fieldCode="AR" term="%22Burballa%2C+Carla%22">Burballa, Carla</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Yuki+Ohkawa%22">Yuki Ohkawa</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Tomohiko+Fukuda%22">Tomohiko Fukuda</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Yoichiro+Harada%22">Yoichiro Harada</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Curwin%2C+Amy+J%2E%22">Curwin, Amy J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Brouwers%2C+Nathalie%22">Brouwers, Nathalie</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Thun%2C+Gian+A%2E%22">Thun, Gian A.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Jianguo+Gu%22">Jianguo Gu</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Gut%2C+Ivo%22">Gut, Ivo</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Naoyuki+Taniguchi%22">Naoyuki Taniguchi</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Malhotra%2C+Vivek%22">Malhotra, Vivek</searchLink><relatesTo>1,6,7</relatesTo><i> vivek.malhotra@crg.eu</i>
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  Data: <searchLink fieldCode="DE" term="%22Mucins%22">Mucins</searchLink><br /><searchLink fieldCode="DE" term="%22Ulcerative+colitis%22">Ulcerative colitis</searchLink><br /><searchLink fieldCode="DE" term="%22Alimentary+canal%22">Alimentary canal</searchLink><br /><searchLink fieldCode="DE" term="%22Shearing+force%22">Shearing force</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+membranes%22">Cell membranes</searchLink>
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  Data: Mucins are the main macrocomponents of the mucus layer that protects the digestive tract from pathogens. Fucosylation of mucins increases mucus viscoelasticity and its resistance to shear stress. These properties are altered in patients with ulcerative colitis (UC), which is marked by a chronic inflammation of the distal part of the colon. Here, we show that levels of Fucosyltransferase 8 (FUT8) and specific mucins are increased in the distal inflamed colon of UC patients. Recapitulating this FUT8 overexpression in mucin-producing HT29-18N2 colonic cell line increases delivery of MUC1 to the plasma membrane and extracellular release of MUC2 and MUC5AC. Mucins secreted by FUT8 overexpressing cells are more resistant to removal from the cell surface than mucins secreted by FUT8-depleted cells (FUT8 KD). FUT8 KD causes intracellular accumulation of MUC1 and alters the ratio of secreted MUC2 to MUC5AC. These data fit well with the Fut82/2 mice phenotype, which are protected from UC. Fut82/2 mice exhibit a thinner proximal colon mucus layer with an altered ratio of neutral to acidic mucins. Together, our data reveal that FUT8 modifies the biophysical properties of mucus by controlling levels of cell surface MUC1 and quantity and quality of secreted MUC2 and MUC5AC. We suggest that these changes in mucus viscoelasticity likely facilitate bacterial-epithelial interactions leading to inflammation and UC progression. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2205277119
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        Text: English
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        Type: general
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      – SubjectFull: Alimentary canal
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      – SubjectFull: Shearing force
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