Alternate subunit assembly diversifies the function of a bacterial toxin

Fowler, Casey C.; Stack, Gabrielle; Jiao, Xuyao; Lara‐Tejero, María; Galán, Jorge E.

doi:10.1038/s41467-019-11592-0

Cited by 27 publications

(65 citation statements)

References 37 publications

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“…Several groups previously established that multiple TT-encoding serovars also encode a homologous binding subunit, artB ( 28 , 31 , 32 ). Therefore, we also assessed the presence of artB to determine the frequency that TT and ArtB are coencoded in a given serovar.…”

Section: Resultsmentioning

confidence: 99%

“…Expression of pltB in S. Typhi was previously shown to occur when cells were grown under conditions that mimic those encountered by intracellular Salmonella ( 30 , 32 ). Therefore, we compared pltB , cdtB , and artB transcript abundances of S. Javiana grown in Luria-Bertani (LB) broth (pH 7) and N-salts minimal medium containing 8 µM Mg 2+ (pH 7).…”

Section: Resultsmentioning

confidence: 99%

“…Multiple investigations into the role of ArtB, a homolog of PltB, have suggested that ArtB can form a functional TT binding subunit ( 16 , 26 , 32 ). Our results suggest a role for ArtB in the diversification of the TT in NTS serovars, as (i) both toxin subunits are coencoded by serovars spanning multiple lineages of S. enterica subsp.…”

Section: Discussionmentioning

confidence: 99%

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The Majority of Typhoid Toxin-Positive Salmonella Serovars Encode ArtB, an Alternate Binding Subunit

Gaballa

Cheng

Harrand

et al. 2021

mSphere

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Salmonella enterica encodes a wide array of virulence factors. One novel virulence factor, an A2B5 toxin known as the typhoid toxin (TT), was recently identified among a variety of S. enterica serovars. While past studies have shown that some serovars encode both the TT (active subunits CdtB and PltA and binding subunit PltB) and a second binding subunit (ArtB), these serovars were thought to be the exception. Here, we show that genes encoding the TT are detected in more than 100 serovars representing distinct phylogenetic lineages of S. enterica subsp. enterica, although clade B and section Typhi are significantly more likely to encode TT genes than serovars from other clades. Furthermore, we show that 81% of these TT-positive serovars also encode artB, suggesting that the cooccurrence of both toxin binding subunits is considerably more common than previously thought. A combination of in silico modeling, bacterial two-hybrid system screening, and tandem affinity purification (TAP) of toxin subunits suggests that ArtB and PltB interact in vitro, at least under some growth conditions. While different growth conditions yielded slightly higher transcript abundances of artB and pltB, both genes had their highest relative transcript abundances when Salmonella was grown under low-Mg2+ conditions, suggesting that ArtB and PltB may compete for inclusion in the TT. Together, our results suggest that ArtB likely plays an important and previously underappreciated role in the biology of the TT produced by typhoidal and nontyphoidal Salmonella. IMPORTANCE While previous reports had suggested that the typhoid toxin (TT) could potentially use ArtB as an alternate binding subunit, this was thought to play a minor role in the evolution and biology of the toxin. In this study, we establish that both TT genes and artB are widespread among Salmonella enterica subsp. enterica, suggesting that TT likely plays a broader role in Salmonella virulence that extends beyond its proposed role in typhoid fever. Furthermore, our data suggest the selective maintenance of both toxin binding subunits, which may compete for inclusion in the holotoxin. Last, our data support the importance of characterizing diverse nontyphoidal Salmonella (NTS) serovars, as the presence of classically defined typhoidal virulence factors among NTS serovars continues to challenge the typhoid-nontyphoid Salmonella paradigm.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Majority of Typhoid Toxin-Positive Salmonella Serovars Encode ArtB, an Alternate Binding Subunit

Gaballa

Cheng

Harrand

et al. 2021

mSphere

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“…The typhoid toxin was originally characterized as utilizing a homopentameric binding subunit of PltB monomers [20], however new evidence suggests that the typhoid toxin can also form a functional holotoxin with a homopentameric binding subunit of ArtB monomers [75,76]. As ArtB and PltB preferentially bind to different sialoglycans on host cells, the use of multiple binding subunits of this toxin was proposed to enable the typhoid toxin to target different tissue types in humans [77], as well as different hosts [76].…”

Section: The Typhoid Toxinmentioning

confidence: 99%

The ADP-Ribosylating Toxins of Salmonella

Cheng

Wiedmann

2019

Toxins

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A number of pathogenic bacteria utilize toxins to mediate disease in a susceptible host. The foodborne pathogen Salmonella is one of the most important and well-studied bacterial pathogens. Recently, whole genome sequence characterizations revealed the presence of multiple novel ADP-ribosylating toxins encoded by a variety of Salmonella serovars. In this review, we discuss both the classical (SpvB) and novel (typhoid toxin, ArtAB, and SboC/SeoC) ADP-ribosylating toxins of Salmonella, including the structure and function of these toxins and our current understanding of their contributions to virulence.

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“…More recently, a comparative genomic approach identified a gene homologous to the typhoid toxin delivery subunit whose phylogenetic distribution tracks with that of the typhoid toxin locus; this finding fueled the discovery that S . Typhi produces two different versions of typhoid toxin that have distinct functionality [ 36 ]. Here, we exploit expanding genomic databases and bioinformatic toolsets to shed light on the function of an uncharacterized S .…”

Section: Introductionmentioning

confidence: 99%

Identification of A Putative T6SS Immunity Islet in Salmonella Typhi

Barretto¹,

Fowler²

2020

Pathogens

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Typhoid fever is a major global health problem and is the result of systemic infections caused by the human-adapted bacterial pathogen Salmonella enterica serovar Typhi (S. Typhi). The pathology underlying S. Typhi infections significantly differ from infections caused by broad host range serovars of the same species, which are a common cause of gastroenteritis. Accordingly, identifying S. Typhi genetic factors that impart functionality absent from broad host range serovars offers insights into its unique biology. Here, we used an in-silico approach to explore the function of an uncharacterized 14-gene S. Typhi genomic islet. Our results indicated that this islet was specific to the S. enterica species, where it was encoded by the Typhi and Paratyphi A serovars, but was generally absent from non-typhoidal serovars. Evidence was gathered using comparative genomics and sequence analysis tools, and indicated that this islet was comprised of Type VI secretion system (T6SS) and contact-dependent growth inhibition (CDI) genes, the majority of which appeared to encode orphan immunity proteins that protected against the activities of effectors and toxins absent from the S. Typhi genome. We herein propose that this islet represents an immune system that protects S. Typhi against competing bacteria within the human gut.

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Alternate subunit assembly diversifies the function of a bacterial toxin

Cited by 27 publications

References 37 publications

The Majority of Typhoid Toxin-Positive Salmonella Serovars Encode ArtB, an Alternate Binding Subunit

The Majority of Typhoid Toxin-Positive Salmonella Serovars Encode ArtB, an Alternate Binding Subunit

The ADP-Ribosylating Toxins of Salmonella

Identification of A Putative T6SS Immunity Islet in Salmonella Typhi

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