Abstract
Attaching/Effacing (A/E) pathogens including enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and the rodent equivalent Citrobacter rodentium are important causative agents of foodborne diseases. Upon infection, a myriad of virulence proteins (effectors) encoded by A/E pathogens are injected through their conserved type III secretion systems (T3SS) into host cells where they interfere with cell signaling cascades, in particular the nuclear factor kappaB (NF-κB) signaling pathway that orchestrates both innate and adaptive immune responses for host defense. Among the T3SS-secreted non-LEE-encoded (Nle) effectors, NleC, a metalloprotease, has been recently elucidated to modulate host NF-κB signaling by cleaving NF-κB Rel subunits. However, it remains elusive how NleC recognizes NF-κB Rel subunits and how the NleC-mediated cleavage impacts on host immune responses in infected cells and animals. In this study, we show that NleC specifically targets p65/RelA through an interaction with a unique N-terminal sequence in p65. NleC cleaves p65 in intestinal epithelial cells, albeit a small percentage of the molecule, to generate the p651–38 fragment during C. rodentium infection in cultured cells. Moreover, the NleC-mediated p65 cleavage substantially affects the expression of a subset of NF-κB target genes encoding proinflammatory cytokines/chemokines, immune cell infiltration in the colon, and tissue injury in C. rodentium-infected mice. Mechanistically, the NleC cleavage-generated p651–38 fragment interferes with the interaction between p65 and ribosomal protein S3 (RPS3), a ‘specifier’ subunit of NF-κB that confers a subset of proinflammatory gene transcription, 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.
Highlights
Foodborne diseases caused by enteric pathogens remain a significant and common health threat and an immense economic burden worldwide [1]
We have found that NleC, a metalloprotease effector secreted by A/E pathogens, modulates host NF-κB signaling and inflammatory responses through a novel mechanism
The NF-κB signaling pathway is crucial for host defense, as it orchestrates both innate and adaptive immune responses [21]
Summary
Foodborne diseases caused by enteric pathogens remain a significant and common health threat and an immense economic burden worldwide [1]. EPEC, EHEC, and the rodent-specific pathogen Citrobacter rodentium produce characteristic attaching/effacing (A/E) lesions on the host intestinal epithelium after they adhere to these cells [3]. These pathogens translocate a variety of virulence proteins (effectors), through a conserved type III secretion system (T3SS), into intestinal epithelial cells (IECs) to modulate host cell functions to the pathogen’s advantage [4,5]. The target proteins of Nle effectors in host cells have started to be identified [11,12,13,14,15,16,17,18,19,20]; it remains largely unknown how Nle effectors interfere with cell signaling cascades and dampen the immune responses in host cells. The molecular mechanisms through which each of these Nle effectors modulate NF-κB signaling have not been fully elucidated [25,31]
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