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EMBO Rep. 2019 Sep;20(9):e48235. doi: 10.15252/embr.201948235. Epub 2019 Jul 29.

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

Author information

1
CIRI, Centre International de Recherche en Infectiologie, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Univ Lyon, Lyon, France.
2
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique, UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Illkirch, France.
3
Laboratoire de Biochimie et de Biologie Moléculaire, Nouvel Hôpital Civil, Strasbourg, France.
4
Université de Strasbourg, Strasbourg, France.
5
INGESTEM National iPSC Infrastructure, Villejuif, France.
6
LBMC, Laboratoire de Biologie et Modélisation de la cellule, Université Claude Bernard Lyon 1, INSERM U1210, CNRS, UMR5239, École Normale Supérieure de Lyon, Univ Lyon, Lyon, France.
7
Sequencing Platform, Institut de Génomique Fonctionnelle de Lyon (IGFL), Université Claude Bernard Lyon 1, CNRS, UMR5242, École Normale Supérieure de Lyon, Univ Lyon, Lyon, France.
8
BIBS, Bioinformatic and Biostatic Services, CIRI, Lyon, France.

Abstract

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-γ 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.

KEYWORDS:

LPS ; caspase-11; inflammasome; interferon regulatory factor; lipopolysaccharide

PMID:
31353801
PMCID:
PMC6727027
[Available on 2020-09-01]
DOI:
10.15252/embr.201948235

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