Modulation of host signaling in the inflammatory response by enteropathogenic Escherichia coli virulence proteins

Abstract

To successfully infect host cells and evade the host immune response, a type III secretion system (T3SS) is commonly used by enteric bacterial pathogens such as enteropathogenic Escherichia coli (EPEC). Recent findings have revealed that various effectors are injected into host cells through the T3SS and exert an inhibitory effect on inflammatory signaling pathways, subverting the immune responses to these pathogens. Here we review recent studies aimed at addressing the modulation of several important inflammatory signaling pathways modulated by EPEC effector proteins, such as the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, which provides insight into the unfinished work in this unexplored field and helps to identify novel positions in inflammatory signaling networks for EPEC effectors.Cellular & Molecular Immunology advance online publication, 31 October 2016; doi:10.1038/cmi.2016.52.

Figure 1

Diagram summarizing the effects of effector proteins on inflammatory signaling pathways in host cells. The nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways are two main pro-inflammatory signaling pathways targeted and modulated by effector proteins translocated from EPEC into the host cells via the T3SS for immune subversion. Tir spans the host cell membrane with two predicted transmembrane (TM) domains. The central extracellular intimin-binding domain (IBD) is essential for binding to intimin. The phosphorylation of Tyr483/Tyr511 and Tyr 454 recruits SHP1/2 and PI3K, respectively. NleE stabilizes IκB by inactivating TAB2 and TAB3. NleC cleaves the NF-κB subunits and minimizes the activity of p300 and RPS3. NleH1/NleH2 control the activity of RPS3, which confers regulatory specificity on NF-κB-mediated gene expression. NleA blocks NLRP3 inflammasome activation downstream of the NF-κB pathway. NleD directly cleaves p38 and JNK, which are involved in the MAPK signaling pathway. These two pathways are not separated but are linked by certain intermediate proteins, such as TAK1, which means that a more extensive modulatory effect on inflammation may be present. See the text for explanation.