S. typhimurium Encodes an Activator of Rho GTPases that Induces Membrane Ruffling and Nuclear Responses in Host Cells

Abstract

S. typhimurium stimulates signaling pathways leading to membrane ruffling, actin cytoskeleton rearrangements, and nuclear responses. The stimulation requires a protein secretion system (type III) that translocates bacterial proteins into the host cell. We show that SopE, a substrate of this secretion system, stimulates cytoskeletal reorganization and JNK activation in a CDC42- and Rac-1-dependent manner. A lambda gt11 cDNA library screen for proteins that interact with SopE identified Rac-1 and CDC42. Furthermore, purified SopE was shown to stimulate GDP/GTP nucleotide exchange in several Rho GTPases in vitro, including Rac-1 and CDC42. These findings establish a paradigm for microbial stimulation of cellular responses in which the pathogen induces signaling events by directly engaging the signaling machinery within the host cell.

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

“…2). Other toxins influence the activity of Rho GTPases by mimicry of endogenous GAP activity, e.g., Yersinia YopE (von PawelRammingen et al 2000), Salmonella SptP (Fu and Galan 1999), Pseudomonas aeruginosa ExoS (Goehring et al 1999) or endogenous GEF activity, e.g., Salmonella SopE (Hardt et al 1998). Finally, it has been shown recently that Rho GTPase were cleaved proteolytically at the C-terminal isoprenylated cysteine by Yersinia YopT and thereby inactivated (Shao et al 2002(Shao et al , 2003.…”

Biogenesis of Salmonella typhimurium-containing vacuoles in epithelial cells involves interactions with the early endocytic pathway

“…Coupled with its propensity to invade cultured epithelial cells, this makes it an extremely valuable tool for studying invasion and intracellular survival and has enabled the identi®cation and characterization of many of the factors involved (Finlay and Falkow, 1990;Francis et al, 1992;Galan et al, 1992;Ginocchio et al, 1992;1994;Garcia-del Portillo et al, 1993a;1995;Stein et al, 1996;Hardt et al, 1998). Initial contact of Salmonella with an epithelial cell induces host cell signal transduction cascades and extensive cytoskeletal rearrangements, which lead to the formation of membrane ruf¯es on the cell surface (Finlay et al, 1991;Ruschkowski et al, 1992;Francis et al, 1993;Pace et al, 1993).…”

“…Initial contact of Salmonella with an epithelial cell induces host cell signal transduction cascades and extensive cytoskeletal rearrangements, which lead to the formation of membrane ruf¯es on the cell surface (Finlay et al, 1991;Ruschkowski et al, 1992;Francis et al, 1993;Pace et al, 1993). Ruf¯e formation is mediated by a host cellular pathway that is dependent on the small GTP-binding protein CDC42 and a bacterially encoded Rho GTPase activator, and results in the internalization of bacteria into a unique membrane-bound vacuole (Finlay and Falkow, 1990;Garciadel Portillo et al, 1994;Chen et al, 1996;Hardt et al, 1998).…”

SPI-7: Salmonella’s Vi-Encoding Pathogenicity Island

“…SopE was first identified in S. Dublin as a 30 kDa secreted effector protein [39], translocated into target host cells through the Type III Secretion System encoded on SPI-1 [40]. Once inside the cell, SopE interacts with RhoGTPase signalling molecules, promoting guanosine nucleotide exchange [41]. The activated signalling pathways lead to actin rearrangements within the cell, causing membrane ruffling and aiding bacterial invasion [41].…”

“…Once inside the cell, SopE interacts with RhoGTPase signalling molecules, promoting guanosine nucleotide exchange [41]. The activated signalling pathways lead to actin rearrangements within the cell, causing membrane ruffling and aiding bacterial invasion [41].…”