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A genome‐wide screen identifies IRF2 as a key regulator of caspase‐4 in human cells
Author(s) -
Benaoudia Sacha,
Martin Amandine,
Puig Gamez Marta,
Gay Gabrielle,
Lagrange Brice,
Cornut Maxence,
Krasnykov Kyrylo,
Claude JeanBaptiste,
Bourgeois Cyril F,
Hughes Sandrine,
Gillet Benjamin,
Allatif Omran,
Corbin Antoine,
Ricci Romeo,
Henry Thomas
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948235
Subject(s) - pyroptosis , inflammasome , biology , aim2 , microbiology and biotechnology , caspase 1 , cytosol , gene , effector , transcription factor , computational biology , genetics , immunology , biochemistry , inflammation , enzyme
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, IRF 2, is required for pyroptosis following cytosolic LPS delivery and functions by directly regulating caspase‐4 levels in human monocytes and iPSC ‐derived monocytes. CASP 4 , GSDMD , and IRF 2 are the only genes identified with high significance in this screen highlighting the simplicity of the non‐canonical inflammasome. Upon IFN ‐γ priming, IRF 1 induction compensates IRF 2 deficiency, leading to robust caspase‐4 expression. Deficiency in IRF 2 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.