Cited by 176Inflammatory Bowel DiseaseGastrointestinal motility and disordersBarrier Structure and Function Studies

Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis

Open access
Graham, W. Vallen, He, Weiqi, Marchiando, Amanda M., Zha, Juanmin, Singh, Gurminder, Li, Hua-Shan, Biswas, Amlan, Ong, Ma. Lora Drizella M. +13 more·2019·Nature Medicine

Abstract

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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Crossref · 10.1038/s41591-019-0393-7

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  • Treatment with divertin regulates paracellular transport rather than transcellular transport across the membranes.

    “Importantly, they provided the evidence that treatment with divertin regulate paracellular transport rather than transcellular transport across the membranes.”
  • Treatment with divertin blocked acute interferon gamma-primed TNF-induced MLC phosphorylation and barrier loss in Caco-2 monolayers model system.

    “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.”
  • Treatment with divertin reduced the progression and severity of experimental chronic colitis of T cell transfer model by correcting gut permeability.

    “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”
  • Treatment with divertin corrected increased intestinal permeability in IL-10-/- mice (spontaneous colitis model) without significant systemic, mucosal, or epithelial toxicity.

    “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”
  • A domain binding small molecule called "divertin" blocks the recruitment of MLCK1 without inhibiting enzyme function.

    “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”

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Research works printed but not linked: 1

  1. [48]Bricogne G, BUSTER version 2.11.7. (Cambridge, United Kingdom: Global Phasing Ltd., 2017).

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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.
Venue
Nature Medicine
Published
2019-04
Volume
25
Issue
4
Pages
690-700
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
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
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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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