SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCϵ-dependent Pathway

Shu Chen Wei, Hsin Fang Yang-Yen, Po Nien Tsao, Meng Tzu Weng, Chien Chih Tung, Linda C.H. Yu, Liang Chuan Lai, Jen Hao Hsiao, Eric Y. Chuang, Chia Tung Shun, Yen Hsuan Ni, Ramnik J. Xavier, Daniel K. Podolsky, Jeffery J.Y. Yen, Jau Min Wong

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background: The integrity of the gut barrier in patients with inflammatory bowel disease is known to be impaired but the exact mechanisms remain mostly unknown. SHANK3 mutations are associated with autism, and patients with autism are known to have higher proportions of inflammatory bowel disease. Here, we explore the role of SHANK3 in inflammatory bowel disease, both in vivo and in vitro. Methods: Dextran sulfate sodium colitis was induced in SHANK3 knockout mice. Transepithelial electrical resistance, paracellular permeability, and Salmonella invasion assays were used to evaluate epithelial barrier function, in vitro and in vivo. Expression of tight junction proteins, protein kinases, and MAP kinase phosphorylation changes were analyzed by immunoblotting after overexpression or knockdown of SHANK3 expression. SHANK3 expression in intestinal tissue from patients with Crohn's disease was analyzed by quantitative polymerase chain reaction and immunohistochemistry. Results: SHANK3 knockout mice were more susceptible to dextran sulfate sodium. SHANK3 knockout resulted in a leaky epithelial barrier phenotype, as demonstrated by decreased transepithelial electrical resistance, increased paracellular permeability, and increased Salmonella invasion. Overexpression of SHANK3 enhanced ZO-1 expression, and knockdown of SHANK3 resulted in decreased expression of ZO-1. Regulation of ZO-1 expression by SHANK3 seems to be mediated through a PKCϵ-dependent pathway. SHANK3 expression correlated with ZO-1 and PKCϵ in colonic tissue of patients with Crohn's disease. Conclusions: The expression level of SHANK3 affects ZO-1 expression and the barrier function in intestinal epithelial cells. This may provide novel insights in Crohn's disease pathogenesis and treatment.

Original languageEnglish (US)
Pages (from-to)1730-1740
Number of pages11
JournalInflammatory Bowel Diseases
Volume23
Issue number10
DOIs
StatePublished - Oct 1 2017

Keywords

  • autism
  • Crohn's disease
  • epithelial barrier
  • SHANK3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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    Wei, S. C., Yang-Yen, H. F., Tsao, P. N., Weng, M. T., Tung, C. C., Yu, L. C. H., Lai, L. C., Hsiao, J. H., Chuang, E. Y., Shun, C. T., Ni, Y. H., Xavier, R. J., Podolsky, D. K., Yen, J. J. Y., & Wong, J. M. (2017). SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCϵ-dependent Pathway. Inflammatory Bowel Diseases, 23(10), 1730-1740. https://doi.org/10.1097/MIB.0000000000001250