Premium
The cerebral cavernous malformation disease causing gene KRIT1 participates in intestinal epithelial barrier maintenance and regulation
Author(s) -
Wang Yitang,
Li Ye,
Zou Jinjing,
Polster Sean P.,
Lightle Rhonda,
Moore Thomas,
Dimaano Matthew,
He Tong-Chuan,
Weber Christopher R.,
Awad Issam A.,
Shen Le
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201800343r
Subject(s) - barrier function , myosin light chain kinase , gene knockdown , myosin , intestinal epithelium , tight junction , biology , epithelium , microbiology and biotechnology , apoptosis , biochemistry , genetics
Epithelial barrier maintenance and regulation requires an intact perijunctional actomyosin ring underneath the cell‐cell junctions. By searching for known factors affecting the actin cytoskeleton, we identified Krev interaction trapped protein 1 (KRIT1) as a major regulator for epithelial barrier function through multiple mechanisms. KRIT1 is expressed in both small intestinal and colonic epithelium, and KRIT1 knockdown in differentiated Caco‐2 intestinal epithelium decreases epithelial barrier function and increases cation selectivity. KRIT1 knockdown abolished Rho‐associated protein kinase‐induced and myosin II motor inhibitor–induced barrier loss by limiting both small and large molecule permeability but did not affect myosin light chain kinase–induced increases in epithelial barrier function. These data suggest that KRIT1 participates in Rho‐associated protein kinase‐ and myosin II motor–dependent (but not myosin light chain kinase–dependent) epithelial barrier regulation. KRIT1 knockdown exacerbated low‐dose TNF‐induced barrier loss, along with increased cleaved casρase‐3 production. Both events are blocked by pan‐caspase inhibition, indicating that KRIT1 regulates TNF‐induced barrier loss through limiting epithelial apoptosis. These data indicate that KRIT1 controls epithelial barrier maintenance and regulation through multiple pathways, suggesting that KRIT1 mutation in cerebral cavernous malformation disease may alter epithelial function and affect human health.—Wang, Y., Li, Y., Zou, J., Polster, S. P., Lightle, R., Moore, T., Dimaano, M., He, T.‐C., Weber, C. R., Awad, I. A., Shen, L. The cerebral cavernous malformation disease causing gene KRITl participates in intestinal epithelial barrier maintenance and regulation. FASEB J. 33, 2132–2143 (2019). www.fasebj.org