Posttranslational modification of a histone-like protein regulates phenotypic resistance to isoniazid in mycobacteria

Sakatos, Alexandra; Babunovic, Gregory H.; Chase, Michael R.; Dills, Alexander; Leszyk, John D.; Rosebrock, Tracy R.; Bryson, Bryan; Fortune, Sarah M.

doi:10.1126/sciadv.aao1478

Cited by 64 publications

(68 citation statements)

References 58 publications

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“…The genome of DC3000, which is a widely-used strain of Pst , is 6.5 Mb and encodes 5,763 ORFs (Buell et al ., 2003). In addition to 36 type III effectors (T3Es), which contribute to Pst virulence, DC3000 also produces a phytotoxin, coronatine (COR) that induces chlorosis and functions as a jasmonic acid-isoleucine mimic to promote colonization of plants by opening stomata and altering defense signaling pathways (Worley et al ., 2013; Sakatos et al ., 2018; Wei et al ., 2018). By deleting 28 well-expressed T3Es and then reintroducing combinations of multiple effectors back into DC3000, eight effectors were found to be required for near wild-type Pst growth in Nicotiana benthamiana (Cunnac et al ., 2011).…”

Section: Introductionmentioning

confidence: 99%

Natural variation for unusual host responses and flagellin-mediated immunity againstPseudomonas syringaein genetically diverse tomato accessions

Roberts

Mainiero

Powell

et al. 2019

Preprint

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The interaction between tomato and Pseudomonas syringae pv. tomato (Pst) is a well-developed model for investigating the molecular basis of the plant immune system. There is extensive natural variation in Solanum lycopersicum (tomato) but it has not been fully leveraged to enhance our understanding of the tomato-Pst pathosystem. We screened 216 genetically diverse accessions of cultivated tomato and a wild tomato species for natural variation in their response to three strains of Pst. The screen uncovered a broad range of previously unseen host symptoms in response to Pst, and one of these, stem galls, was found to be simply inherited. The screen also identified tomato accessions that showed enhanced responses to flagellin in bacterial population assays and in reactive oxygen species assays upon exposure to flagellin-derived peptides, flg22 and flgII-28. Reporter genes confirmed that the host responses were due primarily to pattern recognition receptor-immunity. This study revealed extensive natural variation in tomato for susceptibility and resistance to Pst and will enable elucidation of the molecular mechanisms underlying these host responses.Key Words: Bacterial speck disease, flagellin, natural variation, NLR-triggered immunity, patterntriggered immunity, plant immunity, PRR-triggered immunity Abramovitch RB, Janjusevic R, Stebbins CE, Martin GB. 2006. Type III effector AvrPtoB requires intrinsic E3 ubiquitin ligase activity to suppress plant cell death and immunity. Proc Natl Acad Sci USA 103: 2851-2856. Abramovitch RB, Kim Y-J, Chen S, Dickman MB, Martin GB. 2003. Pseudomonas type III effector AvrPtoB induces plant disease susceptibility by inhibition of host programmed cell death. EMBO J 22: 60-69. Arredondo CR, Davis RM. 2000. First report of Pseudomonas syringae pv. tomato race 1 on tomato in California. Plant Disease 84: 371. Bao Z, Meng F, Strickler SR, Dunham DM, Munkvold KR, Martin GB. 2015. Identification of a candidate gene in Solanum habrochaites for resistance to a race 1 strain of Pseudomonas syringae pv. tomato. The Plant Genome 8: 10.3835/plantgenome2015.3802.0006. Buell CR, Joardar V, Lindeberg M, Selengut J, Paulsen IT, Gwinn ML, Dodson RJ, Deboy RT, Durkin AS, Kolonay JF, et al. 2003. The complete genome sequence of the Arabidopsis and tomato pathogen Pseudomonas syringae pv. tomato DC3000.

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Section: Introductionmentioning

confidence: 99%

Natural variation for unusual host responses and flagellin-mediated immunity againstPseudomonas syringaein genetically diverse tomato accessions

Roberts

Mainiero

Powell

et al. 2019

Preprint

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“…Together, they are known to regulate the stability and activity of proteins in both eukaryotes and prokaryotes. Lysine acetylation is known to regulate various cellular pathways conserved across species including mycobacteria ( 45, 61 ). Our data also suggest that the cholesterol-mediated growth modulation is triggered by deacetylation of the only lysine residue present in the antitoxin.…”

Section: Discussionmentioning

confidence: 99%

Host cholesterol dependent activation of VapC12 toxin enriches persister population duringMycobacterium tuberculosisinfection

Pandey

Talwar

Pandey

et al. 2019

Preprint

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32A worldwide increase in the frequency of multidrug-resistant and extensively drug-33 resistant cases of tuberculosis is mainly due to therapeutic noncompliance associated 34 with a lengthy treatment regimen. Depending on the drug susceptibility profile, the 35 treatment duration can extend from 6 months to 2 years. This protracted regimen is 36 attributed to a supposedly non-replicating and metabolically inert subset of the 37 Mycobacterium tuberculosis (Mtb) population, called 'persisters'. The mechanism 38 underlying stochastic generation and enrichment of persisters is not fully known. 39 We have previously reported that the utilization of host cholesterol is essential for 40 mycobacterial persistence. In this study, we have demonstrated that cholesterol-41 induced activation of a ribonuclease toxin (VapC12) inhibits translation by 42 targeting proT tRNA in Mtb. This results in cholesterol-specific growth modulation 43 that increases the frequency of the generation of persisters in a heterogeneous Mtb 44 population. Also, a null mutant strain of this toxin (ΔvapC12) failed to persist and 45 demonstrated an enhanced growth phenotype in a guinea pig model of Mtb 46 infection. Thus, we have identified a novel strategy through which cholesterol-47 specific activation of a toxin-antitoxin (TA) module in Mtb enhances persister 48 formation during infection. In addition to identifying the mechanism, the study 49 provides opportunity for targeting persisters, a new paradigm facilitating 50 tuberculosis drug development. 51 52 53 54 55 56 57 58 128the cholesterol-rich media. We have observed a decrease in the replication and metabolic 129 rates of wild-type (WT) H37Rv grown in the cholesterol-rich media by ten-and three-130 fold, respectively, compared with (WT) H37Rv grown in the glycerol-rich media ( Fig. 131 1A, 1B). An in-vitro time-kill curve assay revealed a cholesterol-specific increase in the 132 frequency of the generation of a rifamycin-tolerant sub-population (Fig. 1C). The TA loci 133 across bacterial species regulate growth (21,(29)(30)(31), therefore we speculated the 134 aforementioned phenotype to be regulated by one of the Mtb TA loci. For that we 135 analysed the data of a transposon mutagenesis screening performed in Mtb H37Rv to 136 identify genes essential for growth in a cholesterol-rich environment(32). Through 137

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“…HupB (HU) is a DNA-binding protein, which regulates genome compaction and expression in mycobacteria. Among others, the expression of HupB is affected during the selection pressure of INH in Msmeg [112]. Like many other DNA-binding histone proteins, HupB is also regulated by acetylation, in addition to methylation.…”

Section: Two-component Systemsmentioning

confidence: 99%

Role of post‐translational modifications in the acquisition of drug resistance in Mycobacterium tuberculosis

et al. 2020

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Tuberculosis (TB) is one of the primary causes of deaths due to infectious diseases. The current TB regimen is long and complex, failing of which leads to relapse and/or the emergence of drug resistance. There is a critical need to understand the mechanisms of resistance development. With increasing drug pressure, Mycobacterium tuberculosis (Mtb) activates various pathways to counter drug-related toxicity. Signaling modules steer the evolution of Mtb to a variant that can survive, persist, adapt, and emerge as a form that is resistant to one or more drugs. Recent studies reveal that about 1/3rd of the annotated Mtb proteome is modified post-translationally, with a large number of these proteins being essential for mycobacterial survival. Post-translational modifications (PTMs) such as phosphorylation, acetylation, and pupylation play a salient role in mycobacterial virulence, pathogenesis, and metabolism. The role of many other PTMs is still emerging. Understanding the signaling pathways and PTMs may assist clinical strategies and drug development for Mtb. In this review, we explore the contribution of PTMs to mycobacterial physiology, describe the related cellular processes, and discuss how these processes are linked to drug resistance. A significant number of drug targets, InhA, RpoB, EmbR, and KatG, are modified at multiple residues via PTMs. A better understanding of drug-resistance regulons and associated PTMs will aid in developing effective drugs against TB.

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Posttranslational modification of a histone-like protein regulates phenotypic resistance to isoniazid in mycobacteria

Abstract: A bacterial histone-like protein regulates the formation of privileged, drug-tolerant subpopulations of mycobacteria.

Cited by 64 publications

References 58 publications

Natural variation for unusual host responses and flagellin-mediated immunity againstPseudomonas syringaein genetically diverse tomato accessions

Natural variation for unusual host responses and flagellin-mediated immunity againstPseudomonas syringaein genetically diverse tomato accessions

Host cholesterol dependent activation of VapC12 toxin enriches persister population duringMycobacterium tuberculosisinfection

Role of post‐translational modifications in the acquisition of drug resistance in Mycobacterium tuberculosis

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