PptAB Exports Rgg Quorum-Sensing Peptides in Streptococcus

Chang, Jennifer C.; Federle, Michael J.

doi:10.1371/journal.pone.0168461

Cited by 42 publications

(43 citation statements)

References 34 publications

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“…Relative to the WT parental strain, the ΔpptAB mutant strain is significantly attenuated in ability to cause necrotizing myositis in NHPs (Figure 8, A-D). PptAB has been reported to be required for exporting the SHP2 and SHP3 quorum sensing peptides (71). However, Rgg2, the transcriptional regulator that controls expression of the shp2 and shp3 genes was not identified as important for NHP infections in our TraDIS screens.…”

Section: Resultsmentioning

confidence: 99%

Gene fitness landscape of group A streptococcus during necrotizing myositis

Zhu

Olsen

Beres

et al. 2018

Preprint

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23[ABSTRACT] 24Necrotizing fasciitis and myositis are devastating infections characterized 25 by high mortality. Group A streptococcus (GAS) is a common cause of 26 these infections, but the molecular pathogenesis is poorly understood. We 27 report a genome-wide analysis using serotype M1 and M28 strains that 28 identified novel GAS genes contributing to necrotizing myositis in 29 nonhuman primates (NHP), a clinically relevant model. Using transposon 30 directed insertion-site sequencing (TraDIS) we identified 126 and 116 GAS 31 genes required for infection by serotype M1 and M28 organisms, 32 respectively. For both M1 and M28 strains, more than 25% of the GAS 33 genes required for necrotizing myositis encode known or putative 34 transporters. Thirteen GAS transporters contributed to both M1 and M28 35 strain fitness in NHP myositis, including putative importers for amino 36 acids, carbohydrates, and vitamins, and exporters for toxins, quorum 37 sensing peptides, and uncharacterized molecules. Targeted deletion of 38 genes encoding five transporters confirmed that each isogenic mutant 39 strain was significantly impaired in causing necrotizing myositis in NHPs. 40 qRT-PCR analysis showed that these five genes are expressed in infected 41 NHP and human skeletal muscle. Certain substrate-binding lipoproteins of 42 these transporters, such as Spy0271 and Spy1728, were previously 43 documented to be surface-exposed, suggesting that our findings have 44 translational research implications. 45 46 revealed some of the GAS molecules that contribute to the pathogenesis of 63 necrotizing fasciitis and myositis, including M protein (8, 9), extracellular cysteine 64 protease streptococcal pyrogenic exotoxin B (SpeB) (10-13), hyaluronic acid 65 capsule (14), and cytotoxins NADase and streptolysin O (15-21). However, 66although the genome of GAS is relatively small (~1,800 genes) (22, 23), current 67 understanding of the molecular pathogenesis of GAS necrotizing fasciitis and 68 myositis is limited. 69High-throughput genome-wide screens based on transposon mutagenesis 70 strategies are very useful in providing new information about the genetic basis of 71 bacterial virulence. Technologies such as signature-tagged mutagenesis (STM), 72 transposon site hybridization (TraSH), and Tn-seq have been applied 73 successfully to many bacterial pathogens to identify genes required for fitness 74 under diverse in vivo and ex vivo conditions (24-30). In GAS, genome-wide 75 transposon mutagenesis screens have been used to identify genes contributing 76 to fitness during growth in human blood ex vivo, human saliva ex vivo, and 77 mouse subcutaneous infections (24, 30-32). However, a genome-wide 78 investigation of the GAS genes contributing to fitness in necrotizing myositis has 79 not been undertaken. 80Analysis of the molecular pathogenesis of GAS necrotizing myositis 81 requires use of appropriate animal models. Toward this end, mouse and 82 nonhuman primate (NHP) necrotizing myositis models have been developed that 83 approximate this d...

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Section: Resultsmentioning

confidence: 99%

Gene fitness landscape of group A streptococcus during necrotizing myositis

Zhu

Olsen

Beres

et al. 2018

Preprint

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“…S9). A purely intracellular signaling pathway has been reported for XIP in Streptococcus mutans (14, 41). Such a pathway is unlikely to exist for RtgR/S, since rtg auto-induction requires both PptAB and Ami (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…In the genus Streptococcus, Rgg-family regulators are sometimes associated with short, hydrophobic peptides (SHPs) (12). SHPs are small peptides which are exported by the PptAB transporter (13, 14) and processed into mature pheromones. The Ami oligopeptide importer then internalizes the pheromones back into the cell, where they bind to and modulate the activity of Rgg-family regulators (12).…”

Section: Introductionmentioning

confidence: 99%

Molecular Determinants of Substrate Selectivity of a Pneumococcal Rgg-regulated Peptidase-Containing ABC Transporter

Wang¹,

Medlin

Nguyen

et al. 2019

Preprint

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word count: (abstract/importance: 235/145) 14 Text word count: 4911 15 32 Abstract 33 34 Peptidase-containing ABC transporters (PCATs) are a widely distributed family of 35 transporters which secrete double-glycine (GG) peptides. In the opportunistic pathogen 36 Streptococcus pneumoniae (pneumococcus), the PCATs ComAB and BlpAB have been 37 shown to secrete quorum-sensing pheromones and bacteriocins related to the 38 competence and pneumocin pathways. Here, we describe another pneumococcal 39 PCAT, RtgAB, encoded by the rtg locus and found intact in 17% of strains. The 40 Rgg/SHP-like quorum sensing system RtgR/S, which uses a peptide pheromone with a 41 distinctive Trp-X-Trp motif, regulates expression of the rtg locus and provides a 42 competitive fitness advantage in a mouse model of nasopharyngeal colonization. RtgAB 43 secretes a set of co-regulated rtg GG peptides. ComAB and BlpAB, which share a 44 substrate pool with each other, do not secrete the rtg GG peptides. Similarly, RtgAB 45 does not efficiently secrete ComAB/BlpAB substrates. We examined the molecular 46 determinants of substrate selectivity between ComAB, BlpAB, and RtgAB and found 47 that the GG peptide signal sequences contain all the information necessary to direct 48 secretion through specific transporters. Secretion through ComAB and BlpAB depends 49 largely on the identity of four conserved hydrophobic signal sequence residues 50 previously implicated in substrate recognition by PCATs. In contrast, a motif situated at 51 the N-terminal end of the signal sequence, found only in rtg GG peptides, directs 52 secretion through RtgAB. These findings illustrate the complexity in predicting 53 substrate-PCAT pairings by demonstrating specificity that is not dictated solely by signal 54 sequence residues previously implicated in substrate recognition. 55 56 Importance 57 58The export of peptides from the cell is a fundamental process carried out by all 59 bacteria. One method of bacterial peptide export relies on a family of transporters called 60 peptidase-containing ABC transporters (PCATs). PCATs export so-called GG peptides 61 which carry out diverse functions, including cell-to-cell communication and inter-62 bacterial competition. In this work, we describe a PCAT-encoding genetic locus, rtg, in 63 the pathogen Streptococcus pneumoniae (pneumococcus). The rtg locus is linked to 64 increased competitive fitness advantage in a mouse model of nasopharyngeal 65 colonization. We also describe how the rtg PCAT preferentially secretes a set of co-66 regulated GG peptides but not GG peptides secreted by other pneumococcal PCATs. 67These findings illuminate a relatively understudied part of PCAT biology: how these 68 transporters discriminate between different subsets of GG peptides.

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“…Similarly, LC-MS/MS analysis of supernatants of S. mutans cultures grown to high density [22, 23] showed evidence of XIP. Fourth, a transposon mutagenesis screen in S. pyogenes identified the widely conserved pptAB ABC transporter as a possible exporter of short hydrophobic peptides of the ComS type [24], raising the possibility that S. mutans may also possess a dedicated export mechanism for ComS or XIP.…”

Section: Introductionmentioning

confidence: 99%

“…Although there is evidence that the Eep membrane protease facilitates the processing of S. thermophilus ComS [25], Eep was not found to be involved in the processing of S. mutans ComS [22]. Further, although S. mutans possesses a PptAB-like exporter with a fairly high degree of homology to PptAB of S. pyogenes , deletion of pptAB in S. mutans had only a weak effect on competence induction in mid-exponential phase cultures [24]. These findings leave open the question of how ComS is processed to XIP and exported.…”

Section: Introductionmentioning

confidence: 99%