Salmonella Pathogenesis and Processing of Secreted Effectors by Caspase-3

Department of Pediatric Gastroenterology and Nutrition, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02129, USA.
Science (Impact Factor: 33.61). 10/2010; 330(6002):390-3. DOI: 10.1126/science.1194598
Source: PubMed


The enteric pathogen Salmonella enterica serovar Typhimurium causes food poisoning resulting in gastroenteritis. The S. Typhimurium effector Salmonella invasion protein A (SipA) promotes gastroenteritis by functional motifs that trigger either mechanisms of inflammation or bacterial entry. During infection of intestinal epithelial cells, SipA was found to be responsible for the early activation of caspase-3, an enzyme that is required for SipA cleavage at a specific recognition motif that divided the protein into its two functional domains and activated SipA in a manner necessary for pathogenicity. Other caspase-3 cleavage sites identified in S. Typhimurium appeared to be restricted to secreted effector proteins, which indicates that this may be a general strategy used by this pathogen for processing of its secreted effectors.

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    • "Moreover, we have previously reported on the secretion profile of SipA from the ΔsipB non-polar deletion strain, confirming that this strain secretes identical amounts of SipA compared with the parent wild-type S. Typhimurium strain (SL1344). As shown in Fig. 5C and consistent with our prior studies (Lee et al., 2000; Wall et al., 2007; Srikanth et al., 2010) infection with the ΔsipB non-polar deletion mutant failed to disrupt PERP accumulation at the apical surface. Thus, these observations provide important geneticbased evidence to further substantiate our contention that SipA does not need to be translocated into the epithelial cell cytosol but rather acts extracellularly to elicit PERP accumulation. "
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    ABSTRACT: Salmonella enterica Typhimurium induces intestinal inflammation through the activity of type III secreted effector (T3SE) proteins. Our prior results indicate that the secretion of the T3SE SipA and the ability of SipA to induce epithelial cell responses that lead to induction of PMN transepithelial migration are not coupled to its direct delivery into epithelial cells from Salmonella. We therefore tested the hypothesis that SipA interacts with a membrane protein located at the apical surface of intestinal epithelial cells. Employing a split ubiquitin yeast-two-hybrid screen, we identified the tetraspanning membrane protein, PERP (p53-effector related to PMP-22), as a SipA binding partner. SipA and PERP appear to have intersecting activities as we found PERP to be involved in proinflammatory pathways shown to be regulated by SipA. In sum, our studies reveal a critical role for PERP in the pathogenesis of S. Typhimurium, and for the first time demonstrate that SipA, a T3SE protein, can engage a host protein at the epithelial surface. This article is protected by copyright. All rights reserved.
    Cellular Microbiology 12/2014; 17(6). DOI:10.1111/cmi.12406 · 4.92 Impact Factor
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    • "The presence within effectors of short amino acid motifs that are known to stimulate caspase-3 activation , such as the RGD motif, may also contribute to activation , and indeed, an evolutionary conservation of a prokaryotic caspase-3 activity has also been described, which could play a role (Buckley et al., 1999; Bidle et al., 2010). However if, as the evidence suggests, some bacterial pathogens do indeed utilize unique means of targeting such a critical host enzyme, the findings would have wide reaching repercussions outside bacterial infection (Kim et al., 2007; Srikanth et al., 2010). "
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    ABSTRACT: Apoptosis is a critical process that intrinsically links organism survival to its ability to induce controlled death. Thus, functional apoptosis allows organisms to remove perceived threats to their survival by targeting those cells that it determines pose a direct risk. Central to this process are apoptotic caspases, enzymes that form a signaling cascade, converting danger signals via initiator caspases into activation of the executioner caspase, caspase-3. This enzyme begins disassembly of the cell by activating DNA degrading enzymes and degrading the cellular architecture. Interaction of pathogenic bacteria with caspases, and in particular caspase-3, can therefore impact both host cell and bacterial survival. With roles outside cell death such as cell differentiation, control of signaling pathways and immunomodulation also being described for caspase-3, bacterial interactions with caspase-3 may be of far more significance in infection than previously recognized. In this review, we highlight the ways in which bacterial pathogens have evolved to subvert caspase-3 both through effector proteins that directly interact with the enzyme or by modulating pathways that influence its activation and activity.
    Cellular Microbiology 09/2014; 16(12). DOI:10.1111/cmi.12368 · 4.92 Impact Factor
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    • "Activation of the effector protein SipA has been shown to be necessary for induction of HXA3 synthesis and the resulting PMN migration (Figure 2) (72). Remarkably, the mechanism for activating SipA was recently shown to require processing by the host enzyme caspase-3 at a particular cleavage site, resulting in two distinct effector domains (73). Furthermore, the two domains were shown to be functionally different. "
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    ABSTRACT: The human intestinal epithelium consists of a single layer of epithelial cells that forms a barrier against food antigens and the resident microbiota within the lumen. This delicately balanced organ functions in a highly sophisticated manner to uphold the fidelity of the intestinal epithelium and to eliminate pathogenic microorganisms. On the luminal side, this barrier is fortified by a thick mucus layer, and on the serosal side exists the lamina propria containing a resident population of immune cells. Pathogens that are able to breach this barrier disrupt the healthy epithelial lining by interfering with the regulatory mechanisms that govern the normal balance of intestinal architecture and function. This disruption results in a coordinated innate immune response deployed to eliminate the intruder that includes the release of antimicrobial peptides, activation of pattern-recognition receptors, and recruitment of a variety of immune cells. In the case of Salmonella enterica serovar typhimurium (S. typhimurium) infection, induction of an inflammatory response has been linked to its virulence mechanism, the type III secretion system (T3SS). The T3SS secretes protein effectors that exploit the host's cell biology to facilitate bacterial entry and intracellular survival, and to modulate the host immune response. As the role of the intestinal epithelium in initiating an immune response has been increasingly realized, this review will highlight recent research that details progress made in understanding mechanisms underlying the mucosal inflammatory response to Salmonella infection, and how such inflammatory responses impact pathogenic fitness of this organism.
    Frontiers in Immunology 07/2014; 5:311. DOI:10.3389/fimmu.2014.00311
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