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

Nitish Rana; Giuseppe Privitera; Hannah C. Kondolf; Katarzyna Bulek; Susana Lechuga; Carlo De Salvo; Daniele Corridoni; Agne Antanaviciute; Rebecca L. Maywald; Alexander M. Hurtado; Junjie Zhao; Emina H. Huang; Xiaoxia Li; E. Ricky Chan; Alison Simmons; Giorgos Bamias; Derek W. Abbott; Jason D. Heaney; Andrei I. Ivanov; Theresa T. Pizarro

doi:10.1016/j.cell.2021.12.024

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

Nitish Rana, Giuseppe Privitera, Hannah C. Kondolf, Katarzyna Bulek, Susana Lechuga, Carlo De Salvo, Daniele Corridoni, Agne Antanaviciute, Rebecca L. Maywald, Alexander M. Hurtado, Junjie Zhao, Emina H. Huang, Xiaoxia Li, E. Ricky Chan, Alison Simmons, Giorgos Bamias, Derek W. Abbott, Jason D. Heaney, Andrei I. Ivanov, Theresa T. Pizarro

Research output: Contribution to journal › Article › peer-review

82 Scopus citations

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.

Original language	English (US)
Pages (from-to)	283-298.e17
Journal	Cell
Volume	185
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2021.12.024
State	Published - Jan 20 2022
Externally published	Yes

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2021.12.024

Cite this

Rana, N., Privitera, G., Kondolf, H. C., Bulek, K., Lechuga, S., De Salvo, C., Corridoni, D., Antanaviciute, A., Maywald, R. L., Hurtado, A. M., Zhao, J., Huang, E. H., Li, X., Chan, E. R., Simmons, A., Bamias, G., Abbott, D. W., Heaney, J. D., Ivanov, A. I., & Pizarro, T. T. (2022). GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis. Cell, 185(2), 283-298.e17. https://doi.org/10.1016/j.cell.2021.12.024

Rana, N, Privitera, G, Kondolf, HC, Bulek, K, Lechuga, S, De Salvo, C, Corridoni, D, Antanaviciute, A, Maywald, RL, Hurtado, AM, Zhao, J, Huang, EH, Li, X, Chan, ER, Simmons, A, Bamias, G, Abbott, DW, Heaney, JD, Ivanov, AI & Pizarro, TT 2022, 'GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis', Cell, vol. 185, no. 2, pp. 283-298.e17. https://doi.org/10.1016/j.cell.2021.12.024

@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 = "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",

}

TY - JOUR

T1 - GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis

AU - Rana, Nitish

AU - Privitera, Giuseppe

AU - Kondolf, Hannah C.

AU - Bulek, Katarzyna

AU - Lechuga, Susana

AU - De Salvo, Carlo

AU - Corridoni, Daniele

AU - Antanaviciute, Agne

AU - Maywald, Rebecca L.

AU - Hurtado, Alexander M.

AU - Zhao, Junjie

AU - Huang, Emina H.

AU - Li, Xiaoxia

AU - Chan, E. Ricky

AU - Simmons, Alison

AU - Bamias, Giorgos

AU - Abbott, Derek W.

AU - Heaney, Jason D.

AU - Ivanov, Andrei I.

AU - Pizarro, Theresa T.

PY - 2022/1/20

Y1 - 2022/1/20

N2 - 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.

AB - 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.

KW - FAK

KW - GSDMB

KW - GSDMB genetic polymorphisms

KW - Mtx

KW - PDGFA

KW - epithelial organoids

KW - epithelial restitution and repair

KW - focal adhesion kinase

KW - gasdermin B

KW - gasdermins

KW - inflammatory bowel disease

KW - intestinal epithelial cells

KW - methotrexate

KW - platelet-derived growth factor A

KW - resolution of inflammation

KW - single-cell RNA-seq

KW - single-cell profiling

UR - http://www.scopus.com/inward/record.url?scp=85122969544&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85122969544&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.12.024

DO - 10.1016/j.cell.2021.12.024

M3 - Article

C2 - 35021065

AN - SCOPUS:85122969544

SN - 0092-8674

VL - 185

SP - 283-298.e17

JO - Cell

JF - Cell

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this