ArticleGut2023
Tacrolimus-binding protein FKBP8 directs myosin light chain kinase-dependent barrier regulation and is a potential therapeutic target in Crohn's disease.
Article in Gut, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 39 citations in OpenAlex.
- Perioperative gut microbial ecology: a new frontier for improving the prognosis of hepatocellular carcinoma surgery.Precision clinical medicine · 2026Review
- c-Myc-PANK3-EMT axis regulates the structure and function of intestinal barrier in ulcerative colitis.Journal of advanced research · 2026Article
- Molecular diversity of mitochondrial autophagy receptors: context-dependent effects in human health and disease.Cell death discovery · 2026Review
- Temporal transcriptomic profiling identifies core regulators in cytokine-induced gut barrier disruption in differentiated Caco-2 cells.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Coffea arabica pulp aqueous extract exhibits the anti-colitogenic effect in mice: preventive efficacy and possible mechanisms of action.Biological research · 2026Article
- Targeting MLCK1 uncouples immune checkpoint inhibitor-induced colitis from antitumour immunity.Gut · 2026Article
- Gut microbiota-derived tryptophan metabolite indole-3-carboxaldehyde enhances intestinal barrier function via aryl hydrocarbon receptor/AMP-activated protein kinase signaling activation.Animal bioscience · 2026Article
- FK506‑binding proteins as emerging bridges linking proteostasis to multi‑system pathogenesis and therapeutic strategies (Review).International journal of molecular medicine · 2026Review
- An oral engineered cerium-peptide composite microsphere inhibits inflammatory bowel disease and reverses chronic fibrosis.Journal of nanobiotechnology · 2025Article
- Folate Attenuates Ulcerative Colitis via PI3K/AKT/NF-κB/MLCK Axis Inhibition to Restore Intestinal Barrier Integrity.Biology · 2025Article
- Main genetic factors associated with inflammatory bowel diseases and their consequences on intestinal permeability: involvement in gut inflammation.Journal of gastroenterology · 2025Review
- 2bRAD-M reveals circulating microbiome in chronic antibody-mediated rejection (CAMR) and IgA nephropathy (IgAN) after kidney transplantation.BMC microbiology · 2025Article
- Enhancing intestinal epithelial microtubule stability could alleviate IBD symptoms.Cell communication and signaling : CCS · 2025Article
- High-throughput assay for predicting diarrhea risk using a 2D human intestinal stem cell-derived model.Toxicology in vitro : an international journal published in association with BIBRA · 2025Article
- Deciphering the transcriptomic landscape of systemic lupus erythematosus-associated pulmonary arterial hypertension.Respiratory research · 2025Article
- Intestinal Epithelial Tight Junction Barrier Regulation by Novel Pathways.Inflammatory bowel diseases · 2025Review
- Aging and Intestinal Fibrosis: Mechanisms, Implications, and Therapeutic Strategies.Clinical interventions in aging · 2025Review
- Gallic acid serves as an effective therapeutic agent of inflammatory bowel disease: Pharmacological impacts on tight junction-dependent intestinal permeabilityCurrent research in pharmacology and drug discovery · 2025Article
- Balancing Tumor Immunotherapy and Immune-Related Adverse Events: Unveiling the Key Regulators.International journal of molecular sciences · 2024Review
- Protein isoform-centric therapeutics: expanding targets and increasing specificity.Nature reviews. Drug discovery · 2024Review
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
objectiveIntestinal barrier loss is a Crohn's disease (CD) risk factor. This may be related to increased expression and enzymatic activation of myosin light chain kinase 1 (MLCK1), which increases intestinal paracellular permeability and correlates with CD severity. Moreover, preclinical studies have shown that MLCK1 recruitment to cell junctions is required for tumour necrosis factor (TNF)-induced barrier loss as well as experimental inflammatory bowel disease progression. We sought to define mechanisms of MLCK1 recruitment and to target this process pharmacologically.
designProtein interactions between FK506 binding protein 8 (FKBP8) and MLCK1 were assessed in vitro. Transgenic and knockout intestinal epithelial cell lines, human intestinal organoids, and mice were used as preclinical models. Discoveries were validated in biopsies from patients with CD and control subjects.
resultsMLCK1 interacted specifically with the tacrolimus-binding FKBP8 PPI domain. Knockout or dominant negative FKBP8 expression prevented TNF-induced MLCK1 recruitment and barrier loss in vitro. MLCK1-FKBP8 binding was blocked by tacrolimus, which reversed TNF-induced MLCK1-FKBP8 interactions, MLCK1 recruitment and barrier loss in vitro and in vivo. Biopsies of patient with CD demonstrated increased numbers of MLCK1-FKBP8 interactions at intercellular junctions relative to control subjects.
conclusionBinding to FKBP8, which can be blocked by tacrolimus, is required for MLCK1 recruitment to intercellular junctions and downstream events leading to immune-mediated barrier loss. The observed increases in MLCK1 activity, MLCK1 localisation at cell junctions and perijunctional MLCK1-FKBP8 interactions in CD suggest that targeting this process may be therapeutic in human disease. These new insights into mechanisms of disease-associated barrier loss provide a critical foundation for therapeutic exploitation of FKBP8-MLCK1 interactions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.