CHAC1 Is Differentially Expressed in Normal and Cystic Fibrosis Bronchial Epithelial Cells and Regulates the Inflammatory Response Induced by Pseudomonas aeruginosa

Perra, Léa; Balloy, Viviane; Foussignière, Tobias; Moissenet, Didier; Petat, Hortense; Mungrue, Imran N.; Touqui, Lhousseine; Corvol, Harriet; Chignard, Michel; Guillot, Loic

CHAC1 was identified in mammalian cells for the first time in 2009 as a new component of the unfolded protein response (UPR) pathway (11) . This UPR pathway is induced in response to ER stress due to the presence of misfolded proteins in the ER lumen. The UPR consists of three pathways initiated by inositol-requiring enzyme 1α, eukaryotic translation initiation factor 2-α kinase 3 (PERK), and activation transcription factor (ATF) 6 (12). These three pathways alleviate ER stress by decreasing protein synthesis, facilitating protein folding, and increasing protein degradation. CHAC1 is induced by the PERK pathway downstream of ATF4 and the pro-apoptotic factor DNA damage-inducible transcript 3 (DDIT3 also called CHOP) and has been described as necessary and sufficient to induce markers of apoptosis, particularly the cleavage of the apoptotic factor poly(ADP-ribose) polymerase 1 (PARP) (11) . Moreover, CHAC1 can degrade glutathione in the cytosol of mammalian cells through its γ-glutamylcyclotransferase activity (13) . Various studies have shown a link between ER stress and inflammation (12, 14, 15) . In the context of CF, atypical activation of the UPR pathway has been observed; the resulting ER stress can potentiate the inflammatory response (12) . Moreover, the UPR is implicated in the regulation of cytokine production for bacterial infections (16) . The role of CHAC1 in this interplay between ER stress and inflammation in the context of Pa infection has never been investigated.