Membrane interactions and self‐association of components of the Ess/Type <scp>VII</scp> secretion system of <i>Staphylococcus aureus</i>

Jäger, Franziska; Zoltner, Martin; Kneuper, Holger; Hunter, William N.; Palmer, Tracy

doi:10.1002/1873-3468.12065

Cited by 31 publications

(33 citation statements)

References 17 publications

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“…system (73,74). The EccC-related protein EssC SA (75,76) includes a twin-FHA domain that is essential for secretion (77). FHA domains also mediate oligomerization (78)(79)(80).…”

Section: Figmentioning

confidence: 99%

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Sanchez

Ferrell

Chirakos

et al. 2020

mBio

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Pathogenic mycobacteria encounter multiple environments during macrophage infection. Temporally, the bacteria are engulfed into the phagosome, lyse the phagosomal membrane, and interact with the cytosol before spreading to another cell. Virulence factors secreted by the mycobacterial ESX-1 (ESAT-6-system-1) secretion system mediate the essential transition from the phagosome to the cytosol. It was recently discovered that the ESX-1 system also regulates mycobacterial gene expression in Mycobacterium marinum (R. E. Bosserman, T. T. Nguyen, K. G. Sanchez, A. E. Chirakos, et al., Proc Natl Acad Sci U S A 114:E10772–E10781, 2017, https://doi.org/10.1073/pnas.1710167114), a nontuberculous mycobacterial pathogen, and in the human-pathogenic species M. tuberculosis (A. M. Abdallah, E. M. Weerdenburg, Q. Guan, R. Ummels, et al., PLoS One 14:e0211003, 2019, https://doi.org/10.1371/journal.pone.0211003). It is not known how the ESX-1 system regulates gene expression. Here, we identify the first transcription factor required for the ESX-1-dependent transcriptional response in pathogenic mycobacteria. We demonstrate that the gene divergently transcribed from the whiB6 gene and adjacent to the ESX-1 locus in mycobacterial pathogens encodes a conserved transcription factor (MMAR_5438, Rv3863, now espM). We prove that EspM from both M. marinum and M. tuberculosis directly and specifically binds the whiB6-espM intergenic region. We show that EspM is required for ESX-1-dependent repression of whiB6 expression and for the regulation of ESX-1-associated gene expression. Finally, we demonstrate that EspM functions to fine-tune ESX-1 activity in M. marinum. Taking the data together, this report extends the esx-1 locus, defines a conserved regulator of the ESX-1 virulence pathway, and begins to elucidate how the ESX-1 system regulates gene expression. IMPORTANCE Mycobacterial pathogens use the ESX-1 system to transport protein substrates that mediate essential interactions with the host during infection. We previously demonstrated that in addition to transporting proteins, the ESX-1 secretion system regulates gene expression. Here, we identify a conserved transcription factor that regulates gene expression in response to the ESX-1 system. We demonstrate that this transcription factor is functionally conserved in M. marinum, a pathogen of ectothermic animals; M. tuberculosis, the human-pathogenic species that causes tuberculosis; and M. smegmatis, a nonpathogenic mycobacterial species. These findings provide the first mechanistic insight into how the ESX-1 system elicits a transcriptional response, a function of this protein transport system that was previously unknown.

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“…system (73,74). The EccC-related protein EssC SA (75,76) includes a twin-FHA domain that is essential for secretion (77). FHA domains also mediate oligomerization (78)(79)(80).…”

Section: Figmentioning

confidence: 99%

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Sanchez

Ferrell

Chirakos

et al. 2020

mBio

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“…In vivo crosslinking analysis indicated that Ess membrane proteins homo-12 multimerise [52] Although multimerisation of Thermomonospora curvata EccC 13 is controlled by substrate interactions, EssC multimerisation was observed in 14 a strain of S. aureus lacking core Ess components and substrates. [52].…”

mentioning

confidence: 99%

“…[52]. Thus, 15 even if these ATPases show significant sequence homology, there appear to 16 be differences in the control of their assembly and activity.…”

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confidence: 99%

The Enigmatic Esx Proteins: Looking Beyond Mycobacteria

Unnikrishnan

Constantinidou

Palmer

et al. 2017

Trends in Microbiology

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1Bacteria export proteins across membranes using a range of transport 2 machineries. Type VII secretion systems (T7SSs), originally described in 3 mycobacteria, are now known to be widespread across diverse bacterial 4 phyla. Recent studies have characterized secretion components and 5 mechanisms of type VII secretion in pathogenic and environmental bacteria. A 6 variety of functions have been attributed to T7SS substrates, including 7interactions with eukaryotes and with other bacteria. Here, we evaluate the 8 growing body of knowledge on T7SSs, with focus on the non-mycobacterial 9 systems, reviewing their phylogenetic distribution, structure and function in 10 diverse settings. 11 12 3

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“…To determine whether it is an integral membrane protein we washed isolated membranes with urea which removes peripherally bound proteins by denaturation. Fig 2B indicates that a large fraction of TspA-Myc is displaced from the membrane to the cytoplasmic fraction by urea whereas a bona fide integral membrane protein, EssB, is not displaced by this treatment 24, 25, 26 . We conclude that TspA-Myc peripherally interacts with the membrane.…”

Section: Resultsmentioning

confidence: 95%

A membrane-depolarizing toxin substrate of theStaphylococcus aureusType VII secretion system mediates intra-species competition

Ulhuq

Duggan

Guo

et al. 2018

Preprint

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21 22 † for correspondence tracy.palmer@newcastle.ac.uk 23 24 25 26 42 45 proteins that are essential for virulence and immune evasion 1 . The Ess T7SS of 46Staphylococcus aureus is also required for pathogenesis in murine models of infection 2, 3, 4 , 47 and a longitudinal study of persistent S. aureus infection in the airways of a cystic fibrosis 48 patient showed that the ess T7SS genes were highly upregulated during a 13 year timespan 5 . 49It is becoming increasingly apparent, however, that in addition to having anti-eukaryotic 50 activity, the T7SS of firmicutes mediates interbacterial competition 6, 7, 8 . Some strains of S. 51aureus secrete a DNA endonuclease toxin, EsaD 6, 9 , that when overproduced leads to growth 52 inhibition of a sensitive S. aureus strain 6 . Moreover, Streptococcus intermedius exports at 53 least three LXG domain-containing toxins, TelA, TelB and TelC that mediate contact-54 dependent growth inhibition against a range of Gram positive species 7 . 55A large integral membrane ATPase of the FtsK/SpoIIIE family, termed EssC in firmicutes, is a 56 conserved component of all T7SSs and probably energizes protein secretion as well as 57 forming part of the translocation channel 10, 11, 12, 13 . Three further membrane proteins function 58 alongside the ATPase to mediate T7 protein secretion 2, 3, 13, 14, 15 . EsxA, a small secreted 59 protein of the WXG100 family, is a further conserved T7 component that is dependent on the 60 T7SS for its translocation across the membrane 2, 16 . In S. aureus the T7 structural components 61 are encoded at the ess locus. In commonly-studied S. aureus strains including Newman, 62RN6390 and USA300, the T7 substrates EsxB, EsxC, EsxD and EsaD are encoded 63 immediately downstream of essC ( Fig 1A) and are co-regulated with the genes coding for 64 machinery components 2, 3, 6, 9, 17, 18 . With the exception of EsaD the biological activities of these 65 substrates are unknown, although mutational studies have suggested that EsxB and EsxC 66 contribute to persistent infection in a murine abscess model 2, 17 . 67Despite the ess locus forming part of the core S. aureus genome, these four substrate proteins 68 are not conserved across S. aureus isolates, being found in only approximately 50% of a similar decrease in kidney abscess formation as that seen for T7 mutants in Newman and 71 USA300 2, 4, 20 , despite the fact that recognizable homologues of EsxB/EsxC/EsxD/EsaD are 72 not encoded by this strain 19 . This strongly suggests that there are further S. aureus T7 73 substrates that are yet to be identified. Here we have taken an unbiased approach to identify 74 T7 substrates using quantitative proteomic analysis of culture supernatants from S. aureus 75 RN6390 wild type and essC strains. We identify a new substrate, TspA that is encoded 76 distantly from the ess gene cluster and is found in all sequenced S. aureus strains. Further 77 analysis indicates that TspA has a toxic C-terminal domain that depolarizes membranes. 78Using a zebrafish hindbrain ventricle ...

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Membrane interactions and self‐association of components of the Ess/Type VII secretion system of Staphylococcus aureus

Cited by 31 publications

References 17 publications

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

The Enigmatic Esx Proteins: Looking Beyond Mycobacteria

A membrane-depolarizing toxin substrate of theStaphylococcus aureusType VII secretion system mediates intra-species competition

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