Metalloprotease type III effectors that specifically cleave JNK and NF-κB

Two major arms of the inflammatory response are the NF‐κB and c‐Jun N‐terminal kinase (JNK) pathways. Here, we show that enteropathogenic Escherichia coli (EPEC) employs the type III secretion system to target these two signalling arms by injecting host cells with two effector proteins, NleC and NleD. We provide evidence that NleC and NleD are Zn‐dependent endopeptidases that specifically clip and inactivate RelA (p65) and JNK, respectively, thus blocking NF‐κB and AP‐1 activation. We show that NleC and NleD co‐operate and complement other EPEC effectors in accomplishing maximal inhibition of IL‐8 secretion. This is a remarkable example of a pathogen using multiple effectors to manipulate systematically the host inflammatory response signalling network. Enteropathogenic E. coli secretes multiple effector proteins that enable host‐cell colonization. Two effectors, NleC and NleD, are here shown to act as endopeptidases, cleaving p65 and JNK to inhibit the inflammatory response.