Publications
13 results found
Pillay TD, Hettiarachchi SU, Gan J, et al., 2023, Speaking the host language: how Salmonella effector proteins manipulate the host, Microbiology, Vol: 169, Pages: 1-30, ISSN: 1350-0872
Salmonella injects over 40 virulence factors, termed effectors, into host cells to subvert diverse host cellular processes. Of these 40 Salmonella effectors, at least 25 have been described as mediating eukaryotic-like, biochemical post-translational modifications (PTMs) of host proteins, altering the outcome of infection. The downstream changes mediated by an effector's enzymatic activity range from highly specific to multifunctional, and altogether their combined action impacts the function of an impressive array of host cellular processes, including signal transduction, membrane trafficking, and both innate and adaptive immune responses. Salmonella and related Gram-negative pathogens have been a rich resource for the discovery of unique enzymatic activities, expanding our understanding of host signalling networks, bacterial pathogenesis as well as basic biochemistry. In this review, we provide an up-to-date assessment of host manipulation mediated by the Salmonella type III secretion system injectosome, exploring the cellular effects of diverse effector activities with a particular focus on PTMs and the implications for infection outcomes. We also highlight activities and functions of numerous effectors that remain poorly characterized.
Matthews-Palmer T, Gonzalez-Rodriguez N, Calcraft T, et al., 2021, Structure of the cytoplasmic domain of SctV (SsaV) from the Salmonella SPI-2 injectisome and implications for a pH sensing mechanism, Journal of Structural Biology, Vol: 213, ISSN: 1047-8477
Bacterial type III secretion systems assemble the axial structures of both injectisomes and flagella. Injectisome type III secretion systems subsequently secrete effector proteins through their hollow needle into a host, requiring co-ordination. In the Salmonella enterica serovar Typhimurium SPI-2 injectisome, this switch is triggered by sensing the neutral pH of the host cytoplasm. Central to specificity switching is a nonameric SctV protein with an N-terminal transmembrane domain and a toroidal C-terminal cytoplasmic domain. A ‘gatekeeper’ complex interacts with the SctV cytoplasmic domain in a pH dependent manner, facilitating translocon secretion while repressing effector secretion through a poorly understood mechanism. To better understand the role of SctV in SPI-2 translocon-effector specificity switching, we purified full-length SctV and determined its toroidal cytoplasmic region’s structure using cryo-EM. Structural comparisons and molecular dynamics simulations revealed that the cytoplasmic torus is stabilized by its core subdomain 3, about which subdomains 2 and 4 hinge, varying the flexible outside cleft implicated in gatekeeper and substrate binding. In light of patterns of surface conservation, deprotonation, and structural motion, the location of previously identified critical residues suggest that gatekeeper binds a cleft buried between neighboring subdomain 4s. Simulations suggest that a local pH change from 5 to 7.2 stabilizes the subdomain 3 hinge and narrows the central aperture of the nonameric torus. Our results are consistent with a model of local pH sensing at SctV, where pH-dependent dynamics of SctV cytoplasmic domain affect binding of gatekeeper complex.
Yu X, Grabe G, Liu M, et al., 2018, SsaV interacts with SsaL to control the translocon-to-effector switch in the Salmonella SPI-2 type three secretion system, mBio, Vol: 9, ISSN: 2150-7511
Nonflagellar type III secretion systems (nf T3SSs) form a cell surface needle-like structure and an associated translocon that deliver bacterial effector proteins into eukaryotic host cells. This involves a tightly regulated hierarchy of protein secretion. A switch involving SctP and SctU stops secretion of the needle protein. The gatekeeper protein SctW is required for secretion of translocon proteins and controls a second switch to start effector secretion. Salmonella enterica serovar Typhimurium encodes two T3SSs in Salmonella pathogenicity island 1 (SPI-1) and SPI-2. The acidic vacuole containing intracellular bacteria stimulates assembly of the SPI-2 T3SS and its translocon. Sensing the nearly neutral host cytosolic pH is required for effector translocation. Here, we investigated the involvement of SPI-2-encoded proteins SsaP (SctP), SsaU (SctU), SsaV (SctV), and SsaL (SctW) in regulation of secretion. We found that SsaP and SsaU are involved in the first but not the second secretion switch. A random-mutagenesis screen identified amino acids of SsaV that regulate translocon and effector secretion. Single substitutions in subdomain 4 of SsaV or InvA (SPI-1-encoded SctV) phenocopied mutations of their corresponding gatekeepers with respect to translocon and effector protein secretion and host cell interactions. SsaL interacted with SsaV in bacteria exposed to low ambient pH but not after the pH was raised to 7.2. We propose that SsaP and SsaU enable the apparatus to become competent for a secretion switch and facilitate the SsaL-SsaV interaction. This mediates secretion of translocon proteins until neutral pH is sensed, which causes their dissociation, resulting in arrest of translocon secretion and derepression of effector translocation.IMPORTANCE Salmonella Typhimurium is an intracellular pathogen that uses the SPI-2 type III secretion system to deliver virulence proteins across the vacuole membrane surrounding intracellular bacteria. This involves a tightly re
Yu XJ, Liu M, Holden D, 2016, Salmonella Effectors SseF and SseG Interact with Mammalian Protein ACBD3 (GCP60) To Anchor Salmonella-Containing Vacuoles at the Golgi Network, mBio, Vol: 7, ISSN: 2161-2129
Following infection of mammalian cells, Salmonella enterica serovar Typhimurium (S. Typhimurium) replicates within membrane-bound compartments known as Salmonella-containing vacuoles (SCVs). The Salmonella pathogenicity island 2 type III secretion system (SPI-2 T3SS) translocates approximately 30 different effectors across the vacuolar membrane. SseF and SseG are two such effectors that are required for SCVs to localize close to the Golgi network in infected epithelial cells. In a yeast two-hybrid assay, SseG and an N-terminal variant of SseF interacted directly with mammalian ACBD3, a multifunctional cytosolic Golgi network-associated protein. Knockdown of ACBD3 by small interfering RNA (siRNA) reduced epithelial cell Golgi network association of wild-type bacteria, phenocopying the effect of null mutations of sseG or sseF. Binding of SseF to ACBD3 in infected cells required the presence of SseG. A single-amino-acid mutant of SseG and a double-amino-acid mutant of SseF were obtained that did not interact with ACBD3 in Saccharomyces cerevisiae. When either of these was produced together with the corresponding wild-type effector by Salmonella in infected cells, they enabled SCV-Golgi network association and interacted with ACBD3. However, these properties were lost and bacteria displayed an intracellular replication defect when cells were infected with Salmonella carrying both mutant genes. Knockdown of ACBD3 resulted in a replication defect of wild-type bacteria but did not further attenuate the growth defect of a ΔsseFG mutant strain. We propose a model in which interaction between SseF and SseG enables both proteins to bind ACBD3, thereby anchoring SCVs at the Golgi network and facilitating bacterial replication.
Xie H-X, Lu J-F, Zhou Y, et al., 2015, Identification and Functional Characterization of the Novel <i>Edwardsiella tarda</i> Effector EseJ, INFECTION AND IMMUNITY, Vol: 83, Pages: 1650-1660, ISSN: 0019-9567
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- Citations: 46
Xie H-X, Lu J-F, Rolhion N, et al., 2014, <i>Edwardsiella tarda</i>-Induced Cytotoxicity Depends on Its Type III Secretion System and Flagellin, INFECTION AND IMMUNITY, Vol: 82, Pages: 3436-3445, ISSN: 0019-9567
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- Citations: 29
Yu X-J, Liu M, Matthews S, et al., 2011, Tandem Translation Generates a Chaperone for the <i>Salmonella</i> Type III Secretion System Protein SsaQ, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 286, Pages: 36098-36107
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- Citations: 29
Yu X-J, McGourty K, Liu M, et al., 2010, pH Sensing by Intracellular <i>Salmonella</i> Induces Effector Translocation, SCIENCE, Vol: 328, Pages: 1040-1043, ISSN: 0036-8075
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- Citations: 137
Linehan SA, Rytkönen A, Yu XJ, et al., 2005, SlyA regulates function of <i>Salmonella</i> pathogenicity island 2 (SPI-2) and expression of SPI-2-associated genes, INFECTION AND IMMUNITY, Vol: 73, Pages: 4354-4362, ISSN: 0019-9567
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- Citations: 68
Yu XJ, Liu M, Holden DW, 2004, SsaM and SpiC interact and regulate secretion of <i>Salmonella</i> Pathogenicity Island 2 type III secretion system effectors and translocators, MOLECULAR MICROBIOLOGY, Vol: 54, Pages: 604-619, ISSN: 0950-382X
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- Citations: 45
Ruiz-Albert J, Mundy R, Yu XJ, et al., 2003, SseA is a chaperone for the SseB and SseD translocon components of the <i>Salmonella</i> pathogenicity-island-2-encoded type III secretion system, MICROBIOLOGY-SGM, Vol: 149, Pages: 1103-1111, ISSN: 1350-0872
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- Citations: 43
Yu XJ, Ruiz-Albert J, Unsworth KE, et al., 2002, SpiC is required for secretion of <i>Salmonella</i> Pathogenicity Island 2 type III secretion system proteins, CELLULAR MICROBIOLOGY, Vol: 4, Pages: 531-540, ISSN: 1462-5814
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- Citations: 61
Ruiz-Albert J, Yu XJ, Beuzón CR, et al., 2002, Complementary activities of SseJ and SifA regulate dynamics of the <i>Salmonella typhimurium</i> vacuolar membrane, MOLECULAR MICROBIOLOGY, Vol: 44, Pages: 645-661, ISSN: 0950-382X
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- Citations: 203
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