Intestinal epithelial Casd1 regulates mucus sialic acid O-acetylation and limits tissue damage from large-intestinal mucosal insults
Recent studies show that intestinal epithelial sialylation is essential for homeostasis, but whether this protection depends on sialic acid O -acetylation is unclear. CAS1 domain-containing protein 1 (Casd1) governs sialic acid O -acetylation, a natural inhibitor of sialidase activity. We hypothesized that epithelial mucin O -acetylation protects the colon by limiting sialidase-mediated mucus degradation and dysbiosis. Human MUC2 and murine Muc2 were richly O -acetylated, while intestinal epithelial-specific Casd1 deletion abolished mucin O -acetylation. Unexpectedly, intestinal epithelial cell (IEC) Casd1 −/− mice maintained normal mucus structure, barrier function, physiology, and overall Muc2 sialylation, with only subtle sex-specific microbiota changes. However, IEC Casd1 −/− mice developed significantly greater ulceration during dextran sulfate sodium colitis and increased cecal and distal colonic injury following Citrobacter rodentium infection despite equivalent pathogen burdens. Thus, epithelial sialic acid O -acetylation is dispensable for baseline mucus homeostasis but critically limits tissue damage during inflammatory and infectious insults.
Authors
- Hongyuan Zhang (ORCID: https://orcid.org/0009-0006-1091-3251)
- Simin Jafaripour (ORCID: https://orcid.org/0000-0002-8739-9880)
- Noah Fancy (ORCID: https://orcid.org/0009-0005-8760-701X)
- Kirk Bergstrom (ORCID: https://orcid.org/0000-0002-0747-9566)
- Negin Kazemian (ORCID: https://orcid.org/0000-0001-6974-5201)
- Bruce Andrew Vallance (ORCID: https://orcid.org/0000-0003-1345-6747)
- Wesley F. Zandberg (ORCID: https://orcid.org/0000-0002-5857-9006)
- Colin R. Parrish (ORCID: https://orcid.org/0000-0002-1836-6655)
- Sepideh Pakpour (ORCID: https://orcid.org/0000-0003-3615-1858)
- Brian R. Wasik (ORCID: https://orcid.org/0000-0001-5442-3883)
- Mackenzie Melvin (ORCID: https://orcid.org/0009-0006-9860-6300)
- Emily Diane Howard
- Qiaochu Liang (ORCID: https://orcid.org/0000-0002-8407-1708)
- Clara A. Letef
- Jackline D W Irungu
- Benjamin Bigiremana
- Daniel Chou (ORCID: https://orcid.org/0009-0003-0160-747X)
- Megan Turluk
- Sanjoy Ghosh
- Caixia Ma
- Nitin
- Madison Schwagele
Institutions
- University of British Columbia (CA)
- Cornell University (US)
- Children's & Women's Health Centre of British Columbia (CA)
- New York State College of Veterinary Medicine (US)
- BC Children's Hospital (CA)
- University of British Columbia, Okanagan Campus (CA)
- Okanagan University College (CA)
Publication Details
- Journal
- iScience
- Published
- 2026-10-29
- DOI
- https://doi.org/10.1016/j.isci.2026.117978
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Michael Smith Health Research BC
- Crohn's and Colitis Canada