X-Box Binding Protein 1 (XBP1s) Is a Critical Determinant of Pseudomonas aeruginosa Homoserine Lactone-Mediated Apoptosis

Pseudomonas aeruginosa infections are associated with high mortality rates and occur in diverse conditions including pneumonias,cystic fibrosis and neutropenia. quorum sensing,mediated by small molecules including n-(3-oxo-dodecanoyl) homoserine lactone (c12),regulates p. aeruginosa growth and virulence. in addition,host cell recognition of c12 initiates multiple signalling responses including cell death. to gain insight into mechanisms of c12-mediated cytotoxicity,we studied the role of endoplasmic reticulum stress in host cell responses to c12. dramatic protection against c12-mediated cell death was observed in cells that do not produce the x-box binding protein 1 transcription factor (xbp1s). the leucine zipper and transcriptional activation motifs of xbp1s were sufficient to restore c12-induced caspase activation in xbp1s-deficient cells,although this polypeptide was not transcriptionally active. the xbp1s polypeptide also regulated caspase activation in cells stimulated with n-(3-oxo-tetradecanoyl) homoserine lactone (c14),produced by yersinia enterolitica and burkholderia pseudomallei,and enhanced homoserine lactone-mediated caspase activation in the presence of endogenous xbp1s. in c12-tolerant cells,responses to c12 including phosphorylation of p38 mapk and eukaryotic initiation factor 2α were conserved,suggesting that c12 cytotoxicity is not heavily dependent on these pathways. in summary,this study reveals a novel and unconventional role for xbp1s in regulating host cell cytotoxic responses to bacterial acyl homoserine lactones. © 2013 valentine et al.