Salmonella effectors: important players modulating host cell function during infection - PubMed (original) (raw)

Review

Salmonella effectors: important players modulating host cell function during infection

Terence A Agbor et al. Cell Microbiol. 2011 Dec.

Abstract

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative facultative food-borne pathogen that causes gastroenteritis in humans. This bacterium has evolved a sophisticated machinery to alter host cell function critical to its virulence capabilities. Central to S. Typhimurium pathogenesis are two Type III secretion systems (T3SS) encoded within pathogenicity islands SPI-1 and SPI-2 that are responsible for the secretion and translocation of a set of bacterial proteins termed effectors into host cells with the intention of altering host cell physiology for bacterial entry and survival. Thus, once delivered by the T3SS, the secreted effectors play critical roles in manipulating the host cell to allow for bacteria invasion, induction of inflammatory responses, and the assembly of an intracellular protective niche created for bacterial survival and replication. Emerging evidence indicates that these effectors are modular proteins consisting of distinct functional domains/motifs that are utilized by the bacteria to activate intracellular signalling pathways modifying host cell function. Also, recently reported are the dual functionality of secreted effectors and the concept of 'terminal reassortment'. Herein, we highlight some of the nascent concepts regarding Salmonella effectors in the context of infection.

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Figures

Figure 1. Salmonella effectors with dual functions

Examples of S. Typhimurium effectors with dual functions, such as SipA and SifA are illustrated. Infection of a cell with S. Typhimurium results in the secretion of SipA (left) and SifA right by the T3SS (red tube protruding from bacteria shows the needle complex). SipA can be secreted within on the extracellular or intracellular milieu. The N-terminus (red) of the protein has been reported to be involved in the activation of mechanisms that promotes PMN transepithelial migration while the C-terminus (blue) has been reported to bind to and bundle actin (Mitra et al., 2000; Wall et al., 2007). At the junction of the two domains (purple) is caspase-3 recognition and cleavage site (DEVD) at amino acid position 431 (Srikanth et al., 2010). This motif is physiologically significant, as a single amino acid substitution to a sequence not recognized by caspase-3 profoundly attenuates the virulence of this pathogen in both in vitro and in vivo models of salmonellosis. SifA (right), on the other hand, has been reported to promote SCV tubulation and activate GTPase signaling (Ohlson et al., 2008; Alto et al., 2006). The N-terminus of the protein (black) has been reported to bind to the cellular protein SKIP (light blue), which in turns binds to kinesin-1 and promotes microtubule motor movement and endosomal tubulation while the C-terminus (purple) of the protein contains a WxxxE motif (yellow), a protein motif present in bacterial effectors that directly mimics activated GTPases. This motif directly binds to GDPRhoA (green) and activates small GTP-RhoA (red star) in addition to downstream GTPase signaling. Separating these two functional domains is a putative caspase-3 cleavage site (DRPD) (Srikanth et al., 2010). Whether SifA is cleaved by caspase-3 on this motif remains to be determined. T3SSE: Type three secretion system effectors.

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Salmonella effectors: important players modulating host cell function during infection - PubMed (original) (raw)