Plectin, a highly versatile cytolinker protein, provides tissues with mechanical stability through the integration of intermediate filaments (IFs) with cell junctions. Here, we hypothesize that plectin-controlled cytoarchitecture is a critical determinant of the intestinal barrier function and homeostasis. Mice lacking plectin in an intestinal epithelial cell (IEC; PleΔIEC) spontaneously developed colitis characterized by extensive detachment of IECs from the basement membrane (BM), increased intestinal permeability, and inflammatory lesions. Moreover, plectin expression was reduced in the colons of ulcerative colitis (UC) patients and negatively correlated with the severity of colitis. Mechanistically, plectin deficiency in IECs led to aberrant keratin filament (KF) network organization and the formation of dysfunctional hemidesmosomes (HDs) and intercellular junctions. In addition, the hemidesmosomal α6β4 integrin (Itg) receptor showed attenuated association with KFs, and protein profiling revealed prominent downregulation of junctional constituents. Consistent with the effects of plectin loss in the intestinal epithelium, plectin-deficient IECs exhibited remarkably reduced mechanical stability and limited adhesion capacity in vitro. Feeding mice with a low-residue liquid diet that reduced mechanical stress and antibiotic treatment successfully mitigated epithelial damage in the PleΔIEC colon.

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Biochemistry and Cell Biology Max F Perutz Laboratories University of Vienna Vienna Austria

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Department of Clinical and Molecular Pathology Faculty of Medicine and Dentistry Palacky University and University Hospital in Olomouc Olomouc Czech Republic

Department of Clinical and Transplant Pathology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Epithelial Physiology Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Department of Gastroenterology and Hepatology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Physics University of Erlangen Nuremberg Erlangen Germany

Department of Radiodiagnostic and Interventional Radiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Institute of Biophysics and Informatics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Pathology University Hospital Ostrava Ostrava Czech Republic

Laboratory of Cell and Developmental Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Cellular and Molecular Immunology Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Integrative Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Technical University of Liberec Faculty of Health Studie Liberec Czech Republic

University of Liberec Faculty of Mechatronics Informatics and Interdisciplinary Studies Liberec Czech Republic

Erratum v

Mucosal Immunol. 2022 Feb;15(2):373. doi: 10.1038/s41385-021-00463-x. PubMed

Erratum v

Mucosal Immunol. 2022 Mar;15(3):529. doi: 10.1038/s41385-022-00501-2. PubMed

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Mechanics of cell sheets: plectin as an integrator of cytoskeletal networks

Plectin-mediated cytoskeletal crosstalk controls cell tension and cohesion in epithelial sheets