Regulatory Evolution Drives Evasion of Host Inflammasomes by Salmonella Typhimurium

Ilyas, Bushra; Mulder, David T.; Little, Dustin J.; Elhenawy, Wael; Banda, María M.; Pérez-Morales, Deyanira; Tsai, Caressa N.; Chau, NM; Bustamante, Vı́ctor H.; Coombes, Brian K.

doi:10.1016/j.celrep.2018.09.078

Cited by 23 publications

(23 citation statements)

References 50 publications

(54 reference statements)

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“…Upon further inspection of the data, we could link this effect not only to PhoPQ, long known to repress flagella expression (Adams et al, 2001), but also to the TCS SsrAB, the master regulator of the SPI-2 regulon (Walthers et al, 2007). Among others, the transcription factor SsrA is responsible for repressing flhDC, encoding the master regulators of the flagellar expression cascade (Ilyas et al, 2018). In our proteomics data, the histidine kinase SsrB was upregulated in the ΔmgrB mutant.…”

Section: The Small Protein Mgrb Contributes To Salmonella Virulencementioning

confidence: 68%

A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence

Venturini

Svensson

Maaß

et al. 2020

Preprint

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Small proteins are an emerging class of gene products with diverse roles in bacterial physiology. However, a full understanding of their importance has been hampered by insufficient genome annotations and a lack of comprehensive characterization in microbes other than Escherichia coli. We have taken an integrative approach to accelerate the discovery of small proteins and their putative virulence-associated functions in Salmonella Typhimurium. We merged the annotated small proteome of Salmonella with new small proteins predicted with in silico and experimental approaches. We then exploited existing and newly generated global datasets that provide information on small open reading frame expression during infection of epithelial cells (dual RNA-seq), contribution to bacterial fitness inside macrophages (TraDIS), and potential engagement in molecular interactions (Grad-seq). This integrative approach suggested a new role for the small protein MgrB beyond its known function in regulating PhoQ. We demonstrate a virulence and motility defect of a Salmonella ΔmgrB mutant and reveal an effect of MgrB in regulating the Salmonella transcriptome and proteome under infection-relevant conditions. Our study highlights the power of interpreting available “omics” datasets with a focus on small proteins, and may serve as a blueprint for a data integration-based survey of small proteins in diverse bacteria.

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Section: The Small Protein Mgrb Contributes To Salmonella Virulencementioning

confidence: 68%

A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence

Venturini

Svensson

Maaß

et al. 2020

Preprint

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“…Chaperone modulation of fT3SS activity may be important when Salmonella encounters environmental conditions in which flagellar gene expression is down-regulated, including during the early stages of host infection (35–38). Our proposed mechanism may also function in related virulence T3SS (vT3SS), as it is compatible with previous observations showing that vT3SS FliJ homologues bind a subset of secretion chaperones, and that loss of this interaction increases effector secretion and renders the T3SS more resistant to pmf collapse (19, 39, 40).…”

Section: Discussionmentioning

confidence: 99%

Chaperone mediated coupling of subunit availability to activation of flagellar Type III Secretion

Bryant¹,

Chung²,

Fraser³

2020

Preprint

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23 24 Keywords 25 bacterial flagella biogenesis; Type III Secretion System; proton motive force; 26 protein export 27 28 Abstract 29 Bacterial flagella are assembled from thousands of protein subunits that are unfolded 30 and exported across the cell membrane by a specialized flagellar Type III Secretion 31 System (fT3SS). Export of subunit cargo is fuelled by the proton motive force (pmf), 76 (FlgN binds FlgK and FlgL, FliT binds FliD, and FliS binds FliC) (4-6). The 77 chaperones then pilot their cognate subunits to the specialized flagellar Type III 78 secretion system (fT3SS) machinery at the base of each flagellum (7-11).79 Chaperone-subunit complexes initially dock at the FliI component of the flagellar 80 export ATPase, which is evolutionarily related to the F1-ATPase (12). Chaperoned 81 subunits are then thought to interact with the integral membrane export gate 82 component FlhA, where chaperones are released and the subunit cargo is unfolded 83 for translocation across the inner membrane, via the FlhAB-FliPQR export gate, into 84 a narrow central channel in the growing flagellum (9-13). Once released from their 85 cognate subunit cargo, the unladen chaperones FlgN and FliT -but not the flagellin 86 chaperone, FliS -are recruited by the FliJ stalk component of the ATPase, which 87 transfers them to newly synthesised cognate cargo to create a local cycle of 88 chaperone-subunit binding at the membrane fT3SS (8). This is thought to promote 89 export of the minor filament subunits that form the hook-filament junction and the 90 filament cap, which are required for initiation of filament assembly (14).91 92 Export of flagellar subunit cargo across the membrane is powered by the pmf and the 93 flagellar ATPase complex(15, 16). Specifically, the ATPase is thought to facilitate 94 unfolding of subunit cargo (17). In addition, analogous to F-and V-type ATPases, 95 ATP hydrolysis is proposed to drive rotation of the ATPase stalk, FliJ, which interacts 96 with the nonameric export gate component, FlhA, converting the gate into a highly 97 efficient proton-protein antiporter that utilises the ΔΨ electric component of the pmf 98 (18). What is unclear is how FliJ activation of the export gate is regulated in the 99 absence of subunit cargo to prevent constitutive proton influx and wasteful 100 dissipation of the pmf. One way in which export gate activation could be regulated is 101 by sequestration of FliJ by other binding partners, specifically the export chaperones 102 FlgN and FliT. A role for chaperones in the regulation of T3SS activity is supported 103 by the finding that the Psuedomonas virulence T3SS chaperone PcrG binds the FliJ 104 homologue, PscO, and that loss of this interaction results in upregulation of effector 105 secretion and renders the T3SS more resistant to pmf collapse (19). These 106 observations suggest that the chaperone-FliJ interaction is central to the regulation of 107 T3SS activity, however, the mechanistic basis of this regulation remains obscure.108 109 Here, we identify point mutant ...

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“…Typhimurium (Knodler et al, ; Knodler et al, ; Sellin et al, ; Rauch et al, ). However, during later stages of infection, Salmonella dampen NAIP‐NLRC4 inflammasome activation by reducing SPI‐1 expression and up‐regulating the more immunologically silent SPI‐2 T3SS (Miao, Mao, et al, ; Zhao et al, ; Pérez‐Morales et al, ; Reyes Ruiz et al, ) and down‐regulating flagellin expression (Cummings, Wilkerson, Bergsbaken, & Cookson, ; Ilyas et al, ). Notably, NLRC4‐driven pyroptosis of macrophages infected with S .…”

Section: The Inflammasome and Salmonella Infectionmentioning

confidence: 99%

“…The NAIP-NLRC4 inflammasome and caspase-11 promote cell death and expulsion of infected IECs from the intestinal mucosa, which reduces the available replicative niches for S. Typhimurium(Knodler et al, 2010;Knodler et al, 2014;Sellin et al, 2014;Rauch et al, 2017). However, during later stages of infection, Salmonella dampen NAIP-NLRC4 inflammasome activation by reducing SPI-1 expression and up-regulating the more immunologically silent SPI-2 T3SSZhao et al, 2016;Pérez- Morales et al, 2017;Reyes Ruiz et al, 2017) and down-regulating flagellin expression(Cummings, Wilkerson, Bergsbaken, & Cookson, 2006;Ilyas et al, 2018). Notably, NLRC4-driven pyroptosis of macrophages infected with S. Typhimurium results in bacterial liberation in vivo and subsequent phagocytosis and killing by neutrophils, which are resistant to NLRC4-mediated pyroptosisChen et al, 2014).…”

mentioning

confidence: 99%

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

Sanchez‐Garrido

Slater

Clements

et al. 2020

Cellular Microbiology

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Enteric pathogen–host interactions occur at multiple interfaces, including the intestinal epithelium and deeper organs of the immune system. Microbial ligands and activities are detected by host sensors that elicit a range of immune responses. Membrane‐bound toll‐like receptors and cytosolic inflammasome pathways are key signal transducers that trigger the production of pro‐inflammatory molecules, such as cytokines and chemokines, and regulate cell death in response to infection. In recent years, the inflammasomes have emerged as a key frontier in the tussle between bacterial pathogens and the host. Inflammasomes are complexes that activate caspase‐1 and are regulated by related caspases, such as caspase‐11, ‐4, ‐5 and ‐8. Importantly, enteric bacterial pathogens can actively engage or evade inflammasome signalling systems. Extracellular, vacuolar and cytosolic bacteria have developed divergent strategies to subvert inflammasomes. While some pathogens take advantage of inflammasome activation (e.g. Listeria monocytogenes, Helicobacter pylori), others (e.g. E. coli, Salmonella, Shigella, Yersinia sp.) deploy a range of virulence factors, mainly type 3 secretion system effectors, that subvert or inhibit inflammasomes. In this review we focus on inflammasome pathways and their immune functions, and discuss how enteric bacterial pathogens interact with them. These studies have not only shed light on inflammasome‐mediated immunity, but also the exciting area of mammalian cytosolic immune surveillance.

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Regulatory Evolution Drives Evasion of Host Inflammasomes by Salmonella Typhimurium

Cited by 23 publications

References 50 publications

A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence

A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence

Chaperone mediated coupling of subunit availability to activation of flagellar Type III Secretion

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

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