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

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Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis

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Graham, W. Vallen, He, Weiqi, Marchiando, Amanda M., Zha, Juanmin, Singh, Gurminder, Li, Hua-Shan, Biswas, Amlan, Ong, Ma. Lora Drizella M., Jiang, Zhi-Hui, Choi, Wangsun, Zuccola, Harmon, Wang, Yitang, Griffith, James, Wu, Jingshing, Rosenberg, Harry J., Wang, Yingmin, Snapper, Scott B., Ostrov, David, Meredith, Stephen C., Miller, Lawrence W., Turner, Jerrold R.·2019·Nature Medicine

DOI 10.1038/s41591-019-0393-7PMC PMC6461392

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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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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: Graham, W. Vallen
He, Weiqi
Zha, Juanmin
Singh, Gurminder
Biswas, Amlan
Choi, Wangsun
Zuccola, Harmon
Wang, Yitang
Rosenberg, Harry J.
Wang, Yingmin
Snapper, Scott B.
Ostrov, David
Meredith, Stephen C.
Miller, Lawrence W.
Turner, Jerrold R.
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2019-04
Volume: 25
Issue: 4
Pages: 690-700
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-019-0393-7
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis

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