MsaB and CodY Interact To Regulate Staphylococcus aureus Capsule in a Nutrient-Dependent Manner

Batte, Justin L.; Sahukhal, Gyan S.; Elasri, Mohamed O.

doi:10.1128/jb.00294-18

Cited by 14 publications

(23 citation statements)

References 66 publications

(141 reference statements)

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“…The chromatin immunoprecipitation assays were performed as previously described (Sengupta, Jain, Wilkinson, & Jayaswal, ), with modifications as previously described (Batte et al, ). Fold change was calculated by the following equation: ( rsaD IP copy #/gyrA IP copy #)/( rsaD input copy #/ gyrA input copy number).…”

Section: Methodsmentioning

confidence: 99%

Analysis of the CodY RNome reveals RsaD as a stress‐responsive riboregulator of overflow metabolism in Staphylococcus aureus

Augagneur

King

Germain-Amiot

et al. 2019

Molecular Microbiology

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In Staphylococcus aureus, the transcription factor CodY modulates the expression of hundreds of genes, including most virulence factors, in response to the availability of key nutrients like GTP and branched‐chain amino acids. Despite numerous studies examining how CodY controls gene expression directly or indirectly, virtually nothing is known about the extent to which CodY exerts its effect through small regulatory RNAs (sRNAs). Herein, we report the first set of sRNAs under the control of CodY. We reveal that staphylococcal sRNA RsaD is overexpressed >20‐fold in a CodY‐deficient strain in three S. aureus clinical isolates and in S. epidermidis. We validated the CodY‐dependent regulation of rsaD and demonstrated that CodY directly represses rsaD expression by binding the promoter. Using a combination of molecular techniques, we show that RsaD posttranscriptionally regulates alsS (acetolactate synthase) mRNA and enzyme levels. We further show that RsaD redirects carbon overflow metabolism, contributing to stationary phase cell death during exposure to weak acid stress. Taken together, our data delineate a role for CodY in controlling sRNA expression in a major human pathogen and indicate that RsaD may integrate nutrient depletion and other signals to mount a response to physiological stress experienced by S. aureus in diverse environments.

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Section: Methodsmentioning

confidence: 99%

Analysis of the CodY RNome reveals RsaD as a stress‐responsive riboregulator of overflow metabolism in Staphylococcus aureus

Augagneur

King

Germain-Amiot

et al. 2019

Molecular Microbiology

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“…In addition to this study, several other studies also reported increased levels of MsaB (also known as CspA) and oxidative stress-response proteins, including thioredoxin (Trx), in staphylococcal infections (29)(30)(31), highlighting their importance in stress response and their role in causing persistent S. aureus infections in the host. In our previous studies, we reported a regulatory role for the msaABCR operon (MsaB) in capsule production (32,33), biofilm development (34), antibiotic resistance (35), and the formation of persister cells in S. aureus (36). On transcriptomic analysis, deletion of the msaABCR operon in the USA300 LAC strain induced differential expression of more than 10 genes that are involved in resisting oxidative stress (36).…”

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confidence: 99%

The msaABCR Operon Regulates the Response to Oxidative Stress in Staphylococcus aureus

2019

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Staphylococcus aureus has evolved a complex regulatory network that controls a multitude of defense mechanisms against the deleterious effects of oxidative stress stimuli, subsequently leading to the pathogen’s survival and persistence in the hosts. Previously, we characterized the msaABCR operon as a regulator of virulence, antibiotic resistance, and the formation of persister cells in S. aureus. Deletion of the msaABCR operon resulted in the downregulation of several genes involved in resistance against oxidative stress. Notably, those included carotenoid biosynthetic genes and the ohr gene, which is involved in resistance against organic hydroperoxides. These findings led us to hypothesize that the msaABCR operon is involved in resisting oxidative stress generated in the presence of both H2O2 and organic hydroperoxides. Here, we report that a protein product of the msaABCR operon (MsaB) transcriptionally regulates the expression of the crtOPQMN operon and the ohr gene to resist in vitro oxidative stresses. In addition to its direct regulation of the crtOPQMN operon and ohr gene, we also show that MsaB is the transcriptional repressor of sarZ (repressor of ohr). Taken together, these results suggest that the msaABCR operon regulates an oxidative stress defense mechanism, which is required to facilitate persistent and recurrent staphylococcal infections. Moving forward, we plan to investigate the role of msaABCR in the persistence of S. aureus under in vivo conditions. IMPORTANCE This study shows the involvement of the msaABCR operon in resisting oxidative stress by Staphylococcus aureus generated under in vitro and ex vivo conditions. We show that MsaB regulates the expression and production of a carotenoid pigment, staphyloxanthin, which is a potent antioxidant in S. aureus. We also demonstrate that MsaB regulates the ohr gene, which is involved in defending against oxidative stress generated by organic hydroperoxides. This study highlights the importance of msaABCR in the survival of S. aureus in the presence of various environmental stimuli that mainly exert oxidative stress. The findings from this study indicate the possibility that msaABCR is involved in the persistence of staphylococcal infections and therefore could be a potential antimicrobial target to overcome recalcitrant staphylococcal infections.

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“…Nevertheless, Rot as well as the DNA binding proteins CodY and SaeR are likely candidates for direct interference with the P cap promoter element. CodY represses many metabolic and virulence genes, including the cap operon (Pohl et al, 2009;Majerczyk et al, 2010), and binding of CodY to the P cap region has been demonstrated (Majerczyk et al, 2010;Batte et al, 2018;Lei and Lee, 2018). The two-component system (TCS) SaeRS regulates a number of virulence factors, with cap being one of the few genes repressed (Steinhuber et al, 2003;Luong et al, 2011;George et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Revisiting the regulation of the capsular polysaccharide biosynthesis gene cluster in Staphylococcus aureus

Keinhörster

Salzer

Duque‐Jaramillo

et al. 2019

Molecular Microbiology

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Summary Capsular polysaccharide (CP) biosynthesis in Staphylococcus aureus is tightly controlled resulting in a heterogeneous phenotype within a population and CP being mainly detectable in nongrowing cells. Expression of the corresponding biosynthesis gene cluster is driven by one promoter element (Pcap). Here, we demonstrate that Pcap contains a main SigB‐dependent promoter. The SigB consensus motif overlaps with a previously described inverted repeat (IR) that is crucial for cap expression. The essentiality of the IR is derived from this region acting as a SigB binding site rather than as an operator site for the proposed cap activators RbsR and MsaB. Furthermore, Pcap contains an extensive upstream region harboring a weak SigA‐dependent promoter and binding sites for cap repressors such as SaeR, CodY and Rot. Heterogeneous CP synthesis is determined by SigB activity and repressor binding to the upstream region. SigB dependency and regulation by the upstream repressors are also sufficient to explain the temporal gene expression pattern at the transcriptional level. However, CP synthesis remains growth phase‐dependent even when transcription is rendered constitutive, suggesting additional posttranscriptional regulatory circuits. Thus, the interference of multiple repressors with SigB‐dependent promoter activity as well as post‐transcriptional mechanisms ensure the appropriate regulation of CP synthesis.

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MsaB and CodY Interact To Regulate Staphylococcus aureus Capsule in a Nutrient-Dependent Manner

Cited by 14 publications

References 66 publications

Analysis of the CodY RNome reveals RsaD as a stress‐responsive riboregulator of overflow metabolism in Staphylococcus aureus

Analysis of the CodY RNome reveals RsaD as a stress‐responsive riboregulator of overflow metabolism in Staphylococcus aureus

The msaABCR Operon Regulates the Response to Oxidative Stress in Staphylococcus aureus

Revisiting the regulation of the capsular polysaccharide biosynthesis gene cluster in Staphylococcus aureus

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