Transglutaminase 3 crosslinks the secreted gel-forming mucus component Mucin-2 and stabilizes the colonic mucus layer

Jack D. A. Sharpen, Brendan Dolan, Elisabeth E. L. Nyström, George M. H. Birchenough, Liisa Arike, Beatriz Martinez-Abad, Malin E. V. Johansson, Gunnar C. Hansson and Christian V. Recktenwald ()
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Jack D. A. Sharpen: University of Gothenburg
Brendan Dolan: University of Gothenburg
Elisabeth E. L. Nyström: University of Gothenburg
George M. H. Birchenough: University of Gothenburg
Liisa Arike: University of Gothenburg
Beatriz Martinez-Abad: University of Gothenburg
Malin E. V. Johansson: University of Gothenburg
Gunnar C. Hansson: University of Gothenburg
Christian V. Recktenwald: University of Gothenburg

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract The colonic mucus layer is organized as a two-layered system providing a physical barrier against pathogens and simultaneously harboring the commensal flora. The factors contributing to the organization of this gel network are not well understood. In this study, the impact of transglutaminase activity on this architecture was analyzed. Here, we show that transglutaminase TGM3 is the major transglutaminase-isoform expressed and synthesized in the colon. Furthermore, intrinsic extracellular transglutaminase activity in the secreted mucus was demonstrated in vitro and ex vivo. Absence of this acyl-transferase activity resulted in faster degradation of the major mucus component the MUC2 mucin and changed the biochemical properties of mucus. Finally, TGM3-deficient mice showed an early increased susceptibility to Dextran Sodium Sulfate-induced colitis. Here, we report that natural isopeptide cross-linking by TGM3 is important for mucus homeostasis and protection of the colon from inflammation, reducing the risk of colitis.

Date: 2022
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DOI: 10.1038/s41467-021-27743-1

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