GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis

被引：148

作者：

Rana, Nitish ^{[1
,2
,3
]}

Privitera, Giuseppe ^{[1
]}

Kondolf, Hannah C. ^{[1
]}

Bulek, Katarzyna ^{[5
]}

Lechuga, Susana ^{[5
]}

De Salvo, Carlo ^{[1
]}

Corridoni, Daniele ^{[8
]}

Antanaviciute, Agne ^{[8
]}

Maywald, Rebecca L. ^{[9
]}

Hurtado, Alexander M. ^{[1
]}

Zhao, Junjie ^{[5
]}

Huang, Emina H. ^{[6
,7
,11
]}

Li, Xiaoxia ^{[5
]}

Chan, E. Ricky ^{[4
]}

Simmons, Alison ^{[8
]}

Bamias, Giorgos ^{[10
]}

Abbott, Derek W. ^{[1
]}

Heaney, Jason D. ^{[9
]}

Ivanov, Andrei I. ^{[5
]}

Pizarro, Theresa T. ^{[1
]}

机构：

[1] Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Dept Physiol, Sch Med, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Dept Biophys, Sch Med, Cleveland, OH 44106 USA

[4] Case Western Reserve Univ, Inst Computat Biol, Sch Med, Cleveland, OH 44106 USA

[5] Cleveland Clin Fdn, Learner Res Inst, Dept Inflammat & Immun, Cleveland, OH 44195 USA

[6] Cleveland Clin, Learner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA

[7] Cleveland Clin, Learner Res Inst, Dept Colon & Rectal Surg, Cleveland, OH 44195 USA

[8] Univ Oxford, John Radcliffe Hosp, MRC Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford, England

[9] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[10] Ethnikon & Kapodistriakon Univ Athens, Laikon Hosp, Acad Dept Gastroenterol, Athens, Greece

[11] Univ Texas Southwestern Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA

来源：

CELL | 2022年 / 185卷 / 02期

关键词：

FOCAL-ADHESION KINASE; MESENCHYMAL TRANSITION; CELL-PROLIFERATION; WOUND REPAIR; EXPRESSION; GENE; CANCER; PROTEIN; ASTHMA; GROWTH;

D O I：

10.1016/j.cell.2021.12.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：283 / +

页数：34

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