A genome-wide screen identifies IRF2 as a key regulator of caspase-4 in human cells

被引：70

作者：

Benaoudia, Sacha ^{[1
]}

Martin, Amandine ^{[1
]}

Gamez, Marta Puig ^{[2
,3
,4
,5
]}

Gay, Gabrielle ^{[1
]}

Lagrange, Brice ^{[1
]}

Cornut, Maxence ^{[1
]}

Krasnykov, Kyrylo ^{[1
]}

Claude, Jean-Baptiste ^{[6
]}

Bourgeois, Cyril F. ^{[6
]}

Hughes, Sandrine ^{[7
]}

Gillet, Benjamin ^{[7
]}

Allatif, Omran ^{[1
,8
]}

Corbin, Antoine ^{[1
,8
]}

Ricci, Romeo ^{[2
,3
,4
,5
]}

Henry, Thomas ^{[1
]}

机构：

[1] Univ Claude Bernard Lyon 1, ENS Lyon, Univ Lyon, CNRS,UMR5308,U1111,Inserm,CIRI, Lyon, France

[2] Univ Strasbourg, Inst Natl Sante & Rech Med U964, UMR 7104, CNRS,IGBMC, Illkirch Graffenstaden, France

[3] Nouvel Hosp Civil, Lab Biochim & Biol Mol, Strasbourg, France

[4] Univ Strasbourg, Strasbourg, France

[5] INGESTEM Natl iPSC Infrastruct, Villejuif, France

[6] Univ Claude Bernard Lyon 1, Univ Lyon, LBMC, INSERM U1210,CNRS,UMR5239,Ecole Normale Super Lyo, Lyon, France

[7] Univ Claude Bernard Lyon 1, Univ Lyon, IGFL, Sequencing Platform,CNRS,UMR5242,Ecole Normale Su, Lyon, France

[8] Bioinformat & Biostat Serv, BIBS, CIRI, Lyon, France

来源：

EMBO REPORTS | 2019年 / 20卷 / 09期

基金：

欧洲研究理事会;

关键词：

caspase-11; inflammasome; interferon regulatory factor; lipopolysaccharide; LPS; NONCANONICAL INFLAMMASOME ACTIVATION; NLRP3; INFLAMMASOME; RECOGNITION; INTERFERON; SEPSIS; RECEPTORS; BACTERIA; MICE; IFN;

D O I：

10.15252/embr.201948235

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：

Caspase-4, the cytosolic LPS sensor, and gasdermin D, its downstream effector, constitute the non-canonical inflammasome, which drives inflammatory responses during Gram-negative bacterial infections. It remains unclear whether other proteins regulate cytosolic LPS sensing, particularly in human cells. Here, we conduct a genome-wide CRISPR/Cas9 screen in a human monocyte cell line to identify genes controlling cytosolic LPS-mediated pyroptosis. We find that the transcription factor, IRF2, is required for pyroptosis following cytosolic LPS delivery and functions by directly regulating caspase-4 levels in human monocytes and iPSC-derived monocytes. CASP4, GSDMD, and IRF2 are the only genes identified with high significance in this screen highlighting the simplicity of the non-canonical inflammasome. Upon IFN-gamma priming, IRF1 induction compensates IRF2 deficiency, leading to robust caspase-4 expression. Deficiency in IRF2 results in dampened inflammasome responses upon infection with Gram-negative bacteria. This study emphasizes the central role of IRF family members as specific regulators of the non-canonical inflammasome.

引用

页数：14

共 66 条

[31] An NLRP7-Containing Inflammasome Mediates Recognition of Microbial Lipopeptides in Human Macrophages [J].