Subversion of Rho GTPases by WxxxE effectors of attaching and effacing pathogens

Richard Bulgin, Gad Frankel, Wellcome Trust
Enteropathogenic E. coli (EPEC), Enterohaemorhagic E. coli (EHEC) and Citrobacter rodentium are constituent members of the attaching and effacing (A/E) pathogens. The A/E group of bacteria are considered to be extracellular pathogens which form characteristic lesions by intimately adhering to host enterocytes and directing the effacement intestinal brush border. EPEC and EHEC are diarrhoeal pathogens, which are a global health burden in developing and industrialised countries respectively.
more » ... respectively. Citrobacter rodentium is a murine pathogen which is an excellent animal model for EPEC and EHEC infection. EPEC, EHEC and C. rodentium conserve a genomic region termed the locus of enterocyte effacement (LEE) which encodes a type 3 secretion system (T3SS), a core set of type 3 secreted effector proteins and the outer membrane adhesin intimin, which are essential for A/E lesion formation. A/E pathogens utilise their T3SSs to translocate dozens of effector proteins directly from the bacteria into host cells. Once translocated these effector proteins modulate a range of eukaryotic signalling pathways including those which regulate the host cell cytoskeleton. An example of this is the T3SS effector Tir which localises to the mammalian plasma membrane, acts as a receptor for intimin and subsequently directs the polymerisation of actin rich pedestals beneath adherent bacteria. Subversion of the eukaryotic cytoskeleton is a strategy employed by a range of bacterial pathogens. Due to the pivotal role of Rho GTPases in regulating actin dynamics they are commonly targeted by bacterial virulence factors. Recently a family of type 3 secreted effector proteins has been defined based on their homology around an invariant tryptophan and glutamic acid residue separated by three variable amino acids (WxxxE). In this study we have identified the EspM family of proteins and EspT as novel WxxxE effectors in the A/E pathogens. We demonstrate that the EspM proteins and EspT are translocated into host cells in a T3SS dependent manner. Once translocat [...]
doi:10.25560/6054 fatcat:x6bkxjedbffv7lybfbgz7whzg4