Analysis of the mechanisms of Salmonella-induced actin assembly during invasion of host cells and intracellular replication

Unsworth, Kate E.; Way, Michael; McNiven, Mark A.; Machesky, Laura M.; Holden, David W.

doi:10.1111/j.1462-5822.2004.00417.x

Cited by 88 publications

(96 citation statements)

References 64 publications

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“…Recent data suggested that WAVE complex induces ruffling but is dispensable for efficient entry, whereas a novel Arp2/3 complex activator, WASH, mediates entry [36]. Activation of the Arp2/3 complex, which initiates actin nucleation and branching, results in membrane ruffling and/or bacterial uptake depending on the Arp2/3 complex activator [37]. Hence, regulation of Rac-and Cdc42-mediated signaling events seems to be crucial for Salmonella to successfully establish infection through a Zipper and a Trigger entry process.…”

Section: Discussionmentioning

confidence: 99%

Rck of Salmonella enterica, subspecies enterica serovar Enteritidis, mediates Zipper-like internalization

et al. 2010

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Salmonella can invade non-phagocytic cells through its type III secretion system (T3SS-1), which induces a Trigger entry process. This study showed that Salmonella enterica, subspecies enterica serovar Enteritidis can also invade cells via the Rck outer membrane protein. Rck was necessary and sufficient to enable non-invasive E. coli and Rckcoated beads to adhere to and invade different cells. Internalization analysis of latex beads coated with different Rck peptides showed that the peptide containing amino acids 140-150 promoted adhesion, whereas amino acids between 150 and 159 modulated invasion. Expression of dominant-negative derivatives and use of specific inhibitors demonstrated the crucial role of small GTPases Rac1 and Cdc42 in activating the Arp2/3 complex to trigger formation of actin-rich accumulation, leading to Rck-dependent internalization. Finally, scanning and transmission electron microscopy with Rck-coated beads and E. coli expressing Rck revealed microvillus-like extensions that formed a Zipper-like structure, engulfing the adherent beads and bacteria. Overall, our results provide new insights into the Salmonella T3SS-independent invasion mechanisms and strongly suggest that Rck induces a Zipper-like entry mechanism. Consequently, Salmonella seems to be the first bacterium found to be able to induce both Zipper and Trigger mechanisms to invade host cells.

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Section: Discussionmentioning

confidence: 99%

Rck of Salmonella enterica, subspecies enterica serovar Enteritidis, mediates Zipper-like internalization

et al. 2010

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“…Cortactin is necessary for S. flexneri entry into host cells, but is not required by S. enterica (58,59). Hyperacetylation of lysine residues within cortactin in the absence of HDAC6 activity can interfere with the ability of cortactin to bind F-actin (57), and this may account for the inhibitory effect of TSA on host cell invasion by S. flexneri, but not S. enterica.…”

Section: Microtubules Are Required For Upec Invasion Of Host Cells-mentioning

confidence: 99%

Uropathogenic Escherichia coli Invades Host Cells via an HDAC6-modulated Microtubule-dependent Pathway

Dhakal

Mulvey

2009

Journal of Biological Chemistry

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Strains of uropathogenic Escherichia coli (UPEC) encode filamentous adhesive organelles called type 1 pili that promote bacterial colonization and invasion of the bladder epithelium. Type 1 pilus-mediated interactions with host receptors, including ␣3␤1 integrin, trigger localized actin rearrangements that lead to internalization of adherent bacteria via a zipper-like mechanism. Here we report that type 1 pilus-mediated bacterial invasion of bladder cells also requires input from host microtubules and histone deacetylase 6 (HDAC6), a cytosolic enzyme that, by deacetylating ␣-tubulin, can alter the stability of microtubules along with the recruitment and directional trafficking of the kinesin-1 motor complex. We found that disruption of microtubules by nocodazole or vinblastine treatment, as well as microtubule stabilization by taxol, inhibited host cell invasion by UPEC, as did silencing of HDAC6 expression or pharmacological inhibition of HDAC6 activity. Invasion did not require two alternate HDAC6 substrates, Hsp90 and cortactin, but was dependent upon the kinesin-1 light chain KLC2 and an upstream activator of HDAC6, aurora A kinase. These results indicate that HDAC6 and microtubules act as vital regulatory elements during the invasion process, possibly via indirect effects on kinesin-1 and associated cargos.

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“…Further studies will be needed to fully understand the mechanism of the manipulation of actin through SteC-host protein interactions. The data presented here provide the missing link between SteC and actin manipulation, explaining how SteC's effects can be independent of the well known route to actin remodeling through Cdc42, Rac, N-WASP, Scar/WAVE, and Arp2/3, which are common targets of pathogens (10). Thus, the phosphorylation of HSP27 represents a novel mechanism for pathogen-induced manipulation of the actin cytoskeleton.…”

Section: Fig 2 Host Cell-specific Modulation Of Cellular Processes mentioning

confidence: 74%

“…SteC has been identified as the sole serine/threonine protein kinase encoded in the Salmonella genome (8), but the target substrates of this kinase within the host are not fully understood, although it has been demonstrated that SteC partially targets the MAP kinase MEK (9). Interestingly, SteC is capable of promoting assembly of an F-actin meshwork around the SCV; this is dependent on its kinase activity but does not require activation of signaling pathways through Rho-associated protein kinase (8), Cdc42, Rac, N-WASP, Scar/WAVE, and Arp2/3 (10). These host signaling proteins are the main targets of T3SS-secreted effectors from many pathogens, including the SPI1 system in Salmonella (11) and Shigella (12).…”

mentioning

confidence: 99%

Global Impact of Salmonella Pathogenicity Island 2-secreted Effectors on the Host Phosphoproteome

Imami

Bhavsar

et al. 2013

Molecular & Cellular Proteomics

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During the late stages of infection, Salmonella secretes numerous effectors through a type III secretion system that is encoded within Salmonella pathogenicity island 2 (SPI2). Despite the importance of SPI2 as a major virulence factor leading to the systemic spread of the bacteria and diseases, a global view of its effects on host responses is still lacking. Here, we measured global impacts of SPI2 effectors on the host phosphorylation and protein expression levels in RAW264.7 and in HeLa cells, as macrophage and nonphagocytic models of infection. We observe that SPI2 effectors differentially modulate the host phosphoproteome and cellular processes (e.g. protein trafficking, cytoskeletal regulation, and immune signaling) in a host cell-dependent manner. Our unbiased approach reveals the involvement of many previously unrecognized proteins, including E3 ligases (HERC4, RanBP2, and RAD18), kinases (CDK, SIK3, and WNK1), and histones (H2B1F, H4, and H15), in late stages of Salmonella infection. Furthermore, from this phosphoproteome analysis and other quantitative screens, we identified HSP27 as a direct in vitro and in vivo molecular target of the only type III secreted kinase, SteC. Using biochemical and cell biological assays, we demonstrate that SteC phosphorylates multiple sites in HSP27 and induces actin rearrangement through this protein. Together, these results provide a broader landscape of host players contributing to specific processes/pathways mediated by SPI2 effectors than was previously appreciated. Molecular &

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Analysis of the mechanisms of Salmonella-induced actin assembly during invasion of host cells and intracellular replication

Cited by 88 publications

References 64 publications

Rck of Salmonella enterica, subspecies enterica serovar Enteritidis, mediates Zipper-like internalization

Rck of Salmonella enterica, subspecies enterica serovar Enteritidis, mediates Zipper-like internalization

Uropathogenic Escherichia coli Invades Host Cells via an HDAC6-modulated Microtubule-dependent Pathway

Global Impact of Salmonella Pathogenicity Island 2-secreted Effectors on the Host Phosphoproteome

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