FHA domains: Phosphopeptide binding and beyond

Almawi, A.W.; Matthews, Lindsay A.; Guarné, Alba

doi:10.1016/j.pbiomolbio.2016.12.003

Cited by 57 publications

(52 citation statements)

References 44 publications

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“…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). We observed a second shift in mobility of the whiB6-espM probe by EMSA with increasing concentrations of EspM MM protein (Fig.…”

Section: Figmentioning

confidence: 68%

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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Section: Figmentioning

confidence: 68%

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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“…The Forkhead-associated domain is a phosphopeptide recognition domain found in some kinases and transcription factors ( 39 ). Mutations in a gene encoding an uncharacterized protein bearing this domain ( pffhd ; PF3D7_0909700) were found in all samples resistant to MMV668399 ( P = 1 × 10 –18 using an accumulative binomial distribution).…”

Section: Transcription Factorsmentioning

confidence: 99%

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

Cowell

Istvan

Lukens

et al. 2018

Science

223

242

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Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

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“…The Forkhead-associated domain is a phosphopeptide recognition domain found in some kinases and transcription factors (46). Mutations in an uncharacterized protein bearing this domain (pffhd, PF3D7_0909700) were found in all samples resistant to MMV668399 (p = 1E-18 using an accumulative binomial distribution).…”

Section: Transcription Factorsmentioning

confidence: 99%

Mapping the malaria parasite drug-able genome usingin vitroevolution and chemogenomics

Cowell

Istvan²,

Lukens

et al. 2017

Preprint

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Chemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.One Sentence Summary: Whole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/139386 doi: bioRxiv preprint first posted online 3 Main Text:Malaria has a disproportionately negative impact on human health because its causal protozoan parasites are adept at changing their genomes to evade antimalarial drugs and the human immune system. A human infection may contain upwards of to 10 12 asexual blood stage parasites.Thus, even with a relatively slow random parasite mutation rate (~10 -9 ), within a few cycles of replication each base in the P. falciparum genome can acquire a random genetic change that may render at least one parasite resistant to the activity of a small molecule or a human-encoded antibody. The recent evolution of artemisinin-resistant parasites in Southeast Asia now threatens a life-saving treatment in addition to malaria control efforts(1).Although this rapid evolution impedes our ability to control the disease, it can also be used to our advantage since in vitro evolution in the presence of known antimalarials followed by whole-genome sequencing of resistant clones can be used to discover important mediators of drug resistance. For example, the kelch13 allele that is associated with artemisinin resistance was first identified in the genome sequence of an in vitro cultured P. falciparum parasite line exposed to sublethal concentrations of dihydroartemisinin in the laboratory(2). This method of resistance evolution can also reveal new antimalarial drug targets(3). Unlike drug targets that are val...

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FHA domains: Phosphopeptide binding and beyond

Cited by 57 publications

References 44 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

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

Mapping the malaria parasite drug-able genome usingin vitroevolution and chemogenomics

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