SseK1 and SseK3 Type III Secretion System Effectors Inhibit NF-κB Signaling and Necroptotic Cell Death in Salmonella-Infected Macrophages

Günster, Regina A.; Matthews, Sophie A.; Holden, David W.; Thurston, Teresa L. M.

doi:10.1128/iai.00010-17

Cited by 64 publications

(123 citation statements)

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“…Absent Absent Related effectors that inhibit NF-κB signalling (Günster, Matthews, Holden, & Thurston, 2017;Kujat Choy et al, 2004;Yang et al, 2015). (Geddes, Worley, Niemann, & Heffron, 2005;Odendall et al, 2012;Poh et al, 2008) PipB SPI-5 STM1088 t1830 (STY1117) SPA1762 Localizes to SCVs and Sifs (Knodler et al, 2003).…”

Section: Stm4157mentioning

confidence: 99%

TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

Johnson

Mylona

Frankel

2018

Cellular Microbiology

136

106

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Although nontyphoidal Salmonella (NTS; including Salmonella Typhimurium) mainly cause gastroenteritis, typhoidal serovars (Salmonella Typhi and Salmonella Paratyphi A) cause typhoid fever, the treatment of which is threatened by increasing drug resistance. Our understanding of S. Typhi infection in human remains poorly understood, likely due to the host restriction of typhoidal strains and the subsequent popularity of the S. Typhimurium mouse typhoid model. However, translating findings with S. Typhimurium across to S. Typhi has some limitations. Notably, S. Typhi has specific virulence factors, including typhoid toxin and Vi antigen, involved in symptom development and immune evasion, respectively. In addition to unique virulence factors, both typhoidal and NTS rely on two pathogenicity-island encoded type III secretion systems (T3SS), the SPI-1 and SPI-2 T3SS, for invasion and intracellular replication. Marked differences have been observed in terms of T3SS regulation in response to bile, oxygen, and fever-like temperatures. Moreover, approximately half of effectors found in S. Typhimurium are either absent or pseudogenes in S. Typhi, with most of the remaining exhibiting sequence variation. Typhoidal-specific T3SS effectors have also been described. This review discusses what is known about the pathogenesis of typhoidal Salmonella with emphasis on unique behaviours and key differences when compared with S. Typhimurium.

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Section: Stm4157mentioning

confidence: 99%

TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

Johnson

Mylona

Frankel

2018

Cellular Microbiology

136

106

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“…A recent report provides evidence that SseK1 and SseK3, but not SseK2, also function as Arg-GlcNAc glycosyltransferases [9]. Mutation of a conserved DxD catalytic motif within SseK1 and SseK3 abrogates their glycosyltransferase activity [9], consistent with findings for NleB1 [7, 8]. These studies describing catalytically important regions of the glycosyltransferases provide opportunities to better understand the function of these novel enzymes [10].…”

Section: Introductionmentioning

confidence: 54%

“…SseK family members show high sequence similarity to NleB1, a T3SS effector protein from enteropathogenic Escherichia coli (EPEC), which functions as an arginine glycosyltransferase and catalyses the addition of N -acetylglucosamine (GlcNAc) to arginine residues of the mammalian signaling adaptors FADD and TRADD, a modification termed Arg-GlcNAcylation [7, 8]. A recent report provides evidence that SseK1 and SseK3, but not SseK2, also function as Arg-GlcNAc glycosyltransferases [9]. Mutation of a conserved DxD catalytic motif within SseK1 and SseK3 abrogates their glycosyltransferase activity [9], consistent with findings for NleB1 [7, 8].…”

Section: Introductionmentioning

confidence: 99%

“…Although well recognised as glycosyltransferases, there are conflicting reports regarding the host substrates of the SseK effectors. One report suggested that recombinant SseK1 modifies recombinant TRADD in vitro [8], whereas a subsequent report suggested SseK1 modifies both TRADD and FADD when co-expressed ectopically in mammalian cell lines [9]. Yet another report using in vitro glycosylation assays suggested that recombinant SseK1 glycosylates GAPDH but not FADD [11].…”

Section: Introductionmentioning

confidence: 99%

“…Yet another report using in vitro glycosylation assays suggested that recombinant SseK1 glycosylates GAPDH but not FADD [11]. SseK3 on the other hand was reported to bind but not modify the E3-ubiquitin ligase TRIM32 [12], and was shown to weakly modify TRADD but not FADD [9]. While these studies provide useful insights, the true role of these effectors is better interrogated through non-biased screens conducted under conditions that reflect endogenous levels of the effectors and host proteins [13].…”

Section: Introductionmentioning

confidence: 99%

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Salmonellaeffectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways

Newson

Scott

Chung

et al. 2018

Preprint

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24 KEYWORDS25 Salmonella, SseK, glycosyltransferase, death receptor signaling 26 2 27 ABSTRACT 28 Strains of Salmonella utilise two distinct type three secretion systems to deliver effector proteins 29 directly into host cells. The Salmonella effectors SseK1 and SseK3 are arginine 30 glycosyltransferases that modify mammalian death domain containing proteins with N-acetyl 31 glucosamine (GlcNAc) when overexpressed ectopically or as recombinant protein fusions. Here, we 32 combined Arg-GlcNAc glycopeptide immunoprecipitation and mass spectrometry to identify host 33 proteins GlcNAcylated by endogenous levels of SseK1 and SseK3 during Salmonella infection. We 34 observed that SseK1 modified the mammalian signaling protein TRADD, but not FADD as 35 previously reported. Overexpression of SseK1 greatly broadened substrate specificity, while ectopic 36 co-expression of SseK1 and TRADD increased the range of modified arginine residues within the 37 death domain of TRADD. In contrast, endogenous levels of SseK3 resulted in modification of the 38 death domains of receptors of the mammalian TNF superfamily, TNFR1 and TRAILR, at residues 39 Arg 376 and Arg 293 respectively. Structural studies on SseK3 showed that the enzyme displays a 40 classic GT-A glycosyltransferase fold and binds UDP-GlcNAc in a narrow and deep cleft with the 41 GlcNAc facing the surface. Together our data suggests that Salmonellae carrying sseK1 and sseK3 42 employ the glycosyltransferase effectors to antagonise different components of death receptor 43 signaling. 44 45 3 46 AUTHOR SUMMARY 47 Many Gram-negative pathogens employ type three secretion systems to translocate specialised 48 bacterial effector proteins into the host cell. The activities of many Salmonella effectors are not well 49 understood, and identifying the host targets of these effectors will lead to a better understanding of 50 Salmonella pathogenesis. The overexpression of effectors in vitro can provide useful insights into 51 their function, but these results may not represent the true biological role of these effectors during 52 infection. In this study, we showed that endogenous levels of two Salmonella effectors target 53 different host death domain containing signaling proteins that are required for inflammatory and 54 cell death signaling. The study developed new tools to study cognate effector interactions and 55 established the important of effector expression levels in defining natural and unnatural interactions. 56 INTRODUCTION57 Pathogenic serovars of Salmonella utilise two type three secretion systems (T3SS), encoded by 58 Salmonella pathogenicity island-1 and -2 (SPI-1 and SPI-2) to deliver distinct cohorts of effector 59 proteins into host cells during infection [1, 2]. These effector proteins subvert normal cellular 60 processes and collectively enable the bacteria to invade and persist within host cells, partially 61 through the manipulation of inflammatory cell signaling and programmed cell death (reviewed in 62 [3, 4]). While the importance of effector translocatio...

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Necroptosis in apical periodontitis: A programmed cell death with multiple roles

Liu

Fan

2023

Journal Cellular Physiology

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Programmed cell death (PCD) has been a research focus for decades and different mechanisms of cell death, such as necroptosis, pyroptosis, ferroptosis, and cuproptosis have been discovered. Necroptosis, a form of inflammatory PCD, has gained increasing attention in recent years due to its critical role in disease progression and development. Unlike apoptosis, which is mediated by caspases and characterized by cell shrinkage and membrane blebbing, necroptosis is mediated by mixed lineage kinase domain‐like protein (MLKL) and characterized by cell enlargement and plasma membrane rupture. Necroptosis can be triggered by bacterial infection, which on the one hand represents a host defense mechanism against the infection, but on the other hand can facilitate bacterial escape and worsen inflammation. Despite its importance in various diseases, a comprehensive review on the involvement and roles of necroptosis in apical periodontitis is still lacking. In this review, we tried to provide an overview of recent progresses in necroptosis research, summarized the pathways involved in apical periodontitis (AP) activation, and discussed how bacterial pathogens induce and regulated necroptosis and how necroptosis would inhibit bacteria. Furthermore, the interplay between various types of cell death in AP and the potential treatment strategy for AP by targeting necroptosis were also discussed.

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SseK1 and SseK3 Type III Secretion System Effectors Inhibit NF-κB Signaling and Necroptotic Cell Death in Salmonella-Infected Macrophages

Cited by 64 publications

References 60 publications

TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

Salmonellaeffectors SseK1 and SseK3 target death domain proteins in the TNF and TRAIL signaling pathways

Necroptosis in apical periodontitis: A programmed cell death with multiple roles

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