Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis.

Autor: Graham WV; Department of Pathology, University of Chicago, Chicago, IL, USA.; Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University, New York, NY, USA., He W; Department of Pathology, University of Chicago, Chicago, IL, USA.; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda Genomic Resource Center, Soochow University, and Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China., Marchiando AM; Department of Pathology, University of Chicago, Chicago, IL, USA., Zha J; Department of Pathology, University of Chicago, Chicago, IL, USA.; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda Genomic Resource Center, Soochow University, and Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China., Singh G; Department of Pathology, University of Chicago, Chicago, IL, USA.; Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Li HS; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda Genomic Resource Center, Soochow University, and Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China., Biswas A; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Ong MLDM; Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Jiang ZH; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda Genomic Resource Center, Soochow University, and Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China., Choi W; Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Zuccola H; Vertex Pharmaceuticals, Boston, MA, USA., Wang Y; Department of Pathology, University of Chicago, Chicago, IL, USA., Griffith J; Vertex Pharmaceuticals, Boston, MA, USA., Wu J; Department of Pathology, University of Chicago, Chicago, IL, USA., Rosenberg HJ; Department of Pathology, University of Chicago, Chicago, IL, USA., Wang Y; Department of Pathology, University of Chicago, Chicago, IL, USA., Snapper SB; Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA., Ostrov D; Department of Pathology, Immunology and Laboratory Medicine, University of Florida, College of Medicine, Gainesville, FL, USA., Meredith SC; Department of Pathology, University of Chicago, Chicago, IL, USA., Miller LW; Department of Chemistry, University of Illinois at Chicago, Chicago, IL, USA., Turner JR; Department of Pathology, University of Chicago, Chicago, IL, USA. jrturner@bwh.harvard.edu.; Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jrturner@bwh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2019 Apr; Vol. 25 (4), pp. 690-700. Date of Electronic Publication: 2019 Apr 01.
DOI: 10.1038/s41591-019-0393-7
Abstrakt: 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.
Databáze: MEDLINE