The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis
Open accessAbstract
Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.
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“Importantly, they provided the evidence that treatment with divertin regulate paracellular transport rather than transcellular transport across the membranes.”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
In the citing paper
“Further, they showed that treatment with divertin blocked acute interferon gamma–primed TNF-induced MLC phosphorylation and barrier loss in Caco-2 monolayers model system.”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
In the citing paper
“Treatment with divertin also reduced the progression and severity of experimental chronic colitis of T cell transfer model (CD4+ effector T cells in immunodeficient mice) by correcting gut permeability.191”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
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“Further, they demonstrated that treatment with divertin corrected increased intestinal permeability in IL-10–/– mice (spontaneous colitis model) without significant systemic, mucosal, or epithelial toxicity.191”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
In the citing paper
“It was shown by the Turner group that a domain binding small molecule called “divertin” blocks the recruitment of MLCK1 without inhibiting enzyme function.191”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
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Cites
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Intestinal mucosal barrier function in health and disease
Turner, J. R. (2009) · Nature reviews. Immunology · doi:10.1038/nri2653 · Cited by 3,952
Self-citationThe Immunoglobulin Superfamily: Domains For Cell Surface Recognition
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The intestinal epithelial barrier: a therapeutic target?
Odenwald, M. A., & Turner, J. R. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.169 · Cited by 1,288
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Regulation of Intestinal Barrier Function by Microbial Metabolites
Ghosh, S., Whitley, C. S., Haribabu, B., & Jala, V. R. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.02.007 · Cited by 835
Paracellular permeability and tight junction regulation in gut health and disease
Horowitz, A., Chánez-Paredes, S. D., Haest, X., & Turner, J. R. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00766-3 · Cited by 748
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Metadata
- Authors
- Graham, W. V., He, W., Marchiando, A. M., Zha, J., Singh, G., Li, H.-S., Biswas, A., Ong, M. L. D. M., Jiang, Z.-H., Choi, W., Zuccola, H., Wang, Y., Griffith, J., Wu, J., Rosenberg, H. J., Wang, Y., Snapper, S. B., Ostrov, D., Meredith, S. C., Miller, L. W., & Turner, J. R.
- Affiliations
- University of Chicago (US)
- Soochow University (CN)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Vertex Pharmaceuticals (United States) (US)
- University of Florida (US)
- University of Illinois Chicago (US)
- Corresponding author
- Turner, Jerrold R.
- ORCID
- Venue
- Nature Medicine
- Published
- 2019-04
- Volume
- 25
- Issue
- 4
- Pages
- 690-700
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6461392
- OpenAlex
- W2933961522
- Cited by
- 176
- References
- 56
- Citations by year
- 2026: 22 · 2025: 20 · 2024: 37 · 2023: 17 · 2022: 26 · 2021: 23 · 2020: 21 · 2019: 9
- FWCI
- 11.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- University of Illinois Chicago
- Funders
- Crohn's and Colitis Foundation (310801)
- National Institute on Aging (R01AG048793)
- National Heart, Lung, and Blood Institute (T32HL007237)
- National Cancer Institute (P30CA014599)
- National Institute of General Medical Sciences (R01GM081030)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK094954, R24DK099803, R01DK068271, P30DK034854, R01DK061931)
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- myosin light chain kinase, epithelial barrier dysfunction, small molecule inhibitors, myosin light chain phosphorylation, inflammatory bowel disease, diarrhea, mucosal homeostasis
- MeSH terms
- Protein Domains, Actomyosin, Animals, Chronic Disease, Homeostasis, Humans, Inflammation, Intestinal Mucosa, Jejunum, Myosin-Light-Chain Kinase, Phosphorylation, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Caco-2 Cells, Myosin Light Chains, Tight Junctions, Intracellular Space, Mice, Small Molecule Libraries
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