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

Fiche publication

Date publication

juillet 2019

Journal

EMBO reports

Auteurs

Membres identifiés du Cancéropôle Est :
Pr RICCI Roméo

Tous les auteurs :
Benaoudia S, Martin A, Puig Gamez M, Gay G, Lagrange B, Cornut M, Krasnykov K, Claude JB, Bourgeois CF, Hughes S, Gillet B, Allatif O, Corbin A, Ricci R, Henry T

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/31353801

Résumé

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.