@article{17fb0482e1a043daa154d76f36e62705,
title = "GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis",
abstract = "Gasdermins are a family of structurally related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic mucosal inflammatory disorders is well established, little is known about its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids but instead point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based focal adhesions dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects, disrupting epithelial restitution/repair, which, altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.",
keywords = "FAK, GSDMB, GSDMB genetic polymorphisms, Mtx, PDGFA, epithelial organoids, epithelial restitution and repair, focal adhesion kinase, gasdermin B, gasdermins, inflammatory bowel disease, intestinal epithelial cells, methotrexate, platelet-derived growth factor A, resolution of inflammation, single-cell RNA-seq, single-cell profiling",
author = "Nitish Rana and Giuseppe Privitera and Kondolf, {Hannah C.} and Katarzyna Bulek and Susana Lechuga and {De Salvo}, Carlo and Daniele Corridoni and Agne Antanaviciute and Maywald, {Rebecca L.} and Hurtado, {Alexander M.} and Junjie Zhao and Huang, {Emina H.} and Xiaoxia Li and Chan, {E. Ricky} and Alison Simmons and Giorgos Bamias and Abbott, {Derek W.} and Heaney, {Jason D.} and Ivanov, {Andrei I.} and Pizarro, {Theresa T.}",
note = "Funding Information: This work was supported by the NIH: DK091222, DK042191, and DK125293 (to T.T.P.), DK108278 and DK126702 (to A.I.I.), AI141350 (to D.W.A.), CA214300 and DK237304 (to E.H.H.), an institutional MSTP T32 GM007250 (to H.C.K.), and the Biorepository and Morphology/Imaging Cores of DK097948 (Cleveland Digestive Diseases Research Core Center). We acknowledge Claudio Fiocchi, Gail West, Danian Che, and Blake Feldman for their supervisory and/or technical support; Asma Nusrat and Chithra Kannachazhath Muraleedharan for their technical assistance with organoid experimentation, and use of the Leica TCS SP8 confocal microscope in the Light Microscopy Imaging Core at CWRU, made available through the Office of Research Infrastructure (NIH-ORIP) shared instrumentation grant S10OD016164. N.R. conceptualized the study, designed/performed experiments, analyzed/interpreted results, and wrote and edited the manuscript. G.P. H.C.K. K.B. J.Z. R.L.M. D.C. and S.L. performed experiments and analyzed/interpreted results. A.A. and E.R.C. were responsible for computational analyses. C.D.S. and A.M.H. performed experiments. E.H.H. A.S. G.B. X.L. D.W.A. and J.D.H. analyzed/interpreted results and provided reagents. A.I.I. designed experiments, analyzed/interpreted results, provided reagents, and edited the manuscript. T.T.P. conceptualized the study, designed experiments, analyzed/interpreted results, provided reagents, and wrote and edited the manuscript. The authors declare no competing interests. Funding Information: This work was supported by the NIH : DK091222 , DK042191 , and DK125293 (to T.T.P.), DK108278 and DK126702 (to A.I.I.), AI141350 (to D.W.A.), CA214300 and DK237304 (to E.H.H.), an institutional MSTP T32 GM007250 (to H.C.K.), and the Biorepository and Morphology/Imaging Cores of DK097948 ( Cleveland Digestive Diseases Research Core Center ). We acknowledge Claudio Fiocchi, Gail West, Danian Che, and Blake Feldman for their supervisory and/or technical support; Asma Nusrat and Chithra Kannachazhath Muraleedharan for their technical assistance with organoid experimentation, and use of the Leica TCS SP8 confocal microscope in the Light Microscopy Imaging Core at CWRU, made available through the Office of Research Infrastructure (NIH-ORIP) shared instrumentation grant S10OD016164 . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2022",
month = jan,
day = "20",
doi = "10.1016/j.cell.2021.12.024",
language = "English (US)",
volume = "185",
pages = "283--298.e17",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}