Metalloprotease NleC suppresses host NF-κB/inflammatory responses by cleaving p65 and interfering with the p65/RPS3 interaction (MPF7P.703)

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (1_Supplement), p.203-203.4
• Main Authors: Hodgson, Andrea, Wier, Eric, Fu, Kai, Sun, Xin, Zheng, Wenxin, Sham, Ho Pan, Yu, Hongbing, Johnson, Kaitlin, Bailey, Scott, Vallance, Bruce, Wan, Fengyi
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.194.Supp.203.4

The NF-κB signaling pathway has long been recognized as a crucial activator and regulator of the innate and adaptive immune responses. More recently, the ribosomal protein, RPS3 has been identified as a non-rel component of NF-κB and functions as a “specifier” protein critical for the induction of selective proinflammatory gene transcription. Attaching/effacing pathogens including enteropathogenic Escherichia coli, enterohemorrhagic E. coli and the rodent equivalent Citrobacter rodentium are important causative agents of foodborne diseases. A/E pathogens have evolved many strategies to evade the host immune response and encode various effector proteins that target NF-κB at different stages. Our work here, demonstrates how the A/E encoded metalloprotease NleC, specifically cleaves the p65 molecule at the N-terminus generating a fragment that is capable of selectively blocking the function of RPS3. This selective blockade of RPS3 results in a dampened immune response following infection, which amplifies the effect of cleaving only a small percentage of p65 to modulate NF-κB-mediated gene expression. Thus, our results reveal a novel mechanism for A/E pathogens to specifically block NF-κB signaling and inflammatory responses by cleaving a small percentage of p65 and targeting the p65/RPS3 interaction in host cells, thus providing novel insights into the pathogenic mechanisms of foodborne diseases.