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

被引:66
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
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
收藏
页数:14
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