RT Journal Article
SR Electronic
T1 The ulcerative colitis associated gene FUT8 regulates the quantity and quality of secreted mucins
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.30.469270
DO 10.1101/2021.11.30.469270
A1 Gerard Cantero-Recasens
A1 Carla Burballa
A1 Yuki Ohkawa
A1 Tomohiko Fukuda
A1 Yoichiro Harada
A1 IBD Character Consortium
A1 Amy Curwin
A1 Nathalie Brouwers
A1 Gian A. Thun
A1 Jianguo Gu
A1 Ivo Gut
A1 Naoyuki Taniguchi
A1 Vivek Malhotra
YR 2021
UL http://biorxiv.org/content/early/2021/11/30/2021.11.30.469270.abstract
AB Fucosylation of mucins, the main macrocomponents of the mucus layer that protects the digestive tract from pathogens, increases their viscoelasticity and shear stress resistance. 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 the levels of Fucosyltransferase 8 (FUT8) and specific mucins are increased in the distal inflamed colon of UC patients compared to normal individuals. Overexpressing FUT8, as observed in UC, in mucin-producing HT29-18N2 colonic cell line increases trafficking of MUC1 to plasma membrane and secretion of MUC2/MUC5AC. FUT8 depletion (FUT8 KD), instead, causes intracellular accumulation of MUC1 and alters the ratio of secreted MUC2 to MUC5AC. Mucins secreted by FUT8 overexpressing cells are more resistant to shear stress compared to mucins secreted by FUT8 KD cells. These data fit well with the Fut8−/− mice phenotype, which are protected against UC. Fut8−/− mice exhibit a thinner proximal colon mucus layer with an altered ratio of neutral to acidic mucins compared to Fut8+/+ mice. Together, these data reveal that FUT8 optimizes the viscoelastic properties of the extracellular mucous by controlling the quantities of mucins secreted.SIGNIFICANCE STATEMENT Mucins, the major components of the mucous barrier that protects our body from pathogens, are heavily glycosylated proteins. Changes their amounts and properties will alter the viscosity of mucous. Here we show that FUT8, a glycosylation enzyme of the Golgi apparatus, can control the viscosity of secreted mucins. Mucin secreting cells of the distal colon express FUT8, but their levels are altered in Ulcerative colitis patients. As a result, mucous produced by these cells is easily washed away, which exposes them to pathogens. We suggest that a defective mucous production is the main cause of initial inflammation observed in disease. Our findings help in understanding how cells control the quality of mucins and provide a means to prevent Ulcerative colitis.Competing Interest StatementThe authors have declared no competing interest.