2. Academic Validation
  3. Goblet cell-expressed microprotein FXYD3 determines gut homeostasis by maintaining mucus barrier integrity

Goblet cell-expressed microprotein FXYD3 determines gut homeostasis by maintaining mucus barrier integrity

  • Cell Rep. 2025 Nov 25;44(11):116502. doi: 10.1016/j.celrep.2025.116502.
Wenjuan Yang 1,  Yue Xue 1,  Peishuo Zhu 1,  Zhinong Jiang 2,  Rukun He 3,  Hengrui Tian 4,  Tao Wang 1,  Peng Xiao 1,  Wenwen Lian 1,  Qian Cao 1,  Yunn-Hwen Gan 5,  Lihua Lai 6,  Qingqing Wang 7
Affiliations

Affiliations

  • 1 Department of Gastroenterology of Sir Run Run Shaw Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, 1369 West Wenyi Road, Hangzhou 311121, P.R. China.
  • 2 Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310009, P.R. China.
  • 3 Department of Physiology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 4 Department of Gastroenterology of Sir Run Run Shaw Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, 1369 West Wenyi Road, Hangzhou 311121, P.R. China; School of Basic Medical Sciences, Henan University, Kaifeng 475004, P.R. China.
  • 5 Department of Biochemistry, Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, MD7, 8 Medical Drive, Singapore 117596, Republic of Singapore.
  • 6 Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. Electronic address: [email protected].
  • 7 Department of Gastroenterology of Sir Run Run Shaw Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, 1369 West Wenyi Road, Hangzhou 311121, P.R. China. Electronic address: [email protected].
PMID: 41187059 DOI: 10.1016/j.celrep.2025.116502
Abstract

The intestinal mucus layer produced by goblet cells is a critical component of innate immunity. The key host factors and regulatory mechanisms controlling goblet cell function in mucus layer formation remain poorly understood. This study identifies a function for the microprotein FXYD domain-containing transport regulator 3 (FXYD3) in goblet cells in regulating mucus layer formation to maintain intestinal homeostasis. Deficiency of FXYD3 in mouse intestinal epithelial cells results in a damaged mucus barrier, leading to dysbiosis and increased susceptibility to colitis. Mechanistically, FXYD3 interacts with endoplasmic reticulum CA2+-ATPase SERCA2 to enhance its pump activity. FXYD3 deficiency causes defects in ER CA2+ homeostasis and Mucin glycosylation, impairing mucus layer integrity. Furthermore, metabolites of gut microbiota, propionate, and butyrate promote FXYD3 expression. In ulcerative colitis patients, FXYD3 expression is significantly downregulated and correlates with disease severity. These findings indicate FXYD3 is a key mediator of host-microbiota interactions for intestinal health.

Keywords

CP: Immunology; FXYD3; SERCA2; goblet cells; mucin glycosylation; mucus barrier.

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