Bioinformatic and mutational studies of related toxin–antitoxin pairs in Mycobacterium tuberculosis predict and identify key functional residues

Tandon, Himani; Sharma, Arun; Wadhwa, Saruchi; Varadarajan, Raghavan; Singh, Ramandeep; Srinivasan, Narayanaswamy

doi:10.1074/jbc.ra118.006814

Cited by 26 publications

(33 citation statements)

References 70 publications

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“…These predictions corroborate previous work that experimentally demonstrated high insulation thus limited crosstalk between these systems in different Vap sub-clusters [197]. Within a sub-cluster, however, possibility for cross-talk increases [196], and has previously been predicated on the identity of the C-terminal (30 amino acids) of at least a few of these VapB antitoxins [198]…”

Section: Interactions With Cognate Antitoxinssupporting

confidence: 88%

“…M. tuberculosis encodes up to 55 different cognate VapBC systems, which were the subject of a recent study that, guided by available crystal structures, made predictions on the amino acids in the interface of each cognate pair [196]. They were able to identify sub-clusters within both toxins and antitoxins that were more likely to contain cross-interacting pairs.…”

Section: Interactions With Cognate Antitoxinsmentioning

confidence: 99%

“…A similar study mined Mycobacterium tuberculosis (Mt) genome sequences and identified both VapB orphan antitoxins and VapC orphan toxins [196]. The orphan toxins were more closely related to other paralogous toxins, whereas the orphan antitoxins were not similar to other known antitoxins.…”

Section: Orphan Antitoxinsmentioning

confidence: 99%

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Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems

Holt

Ruan

2020

Toxins

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The diversity of Type-II toxin–antitoxin (TA) systems in bacterial genomes requires tightly controlled interaction specificity to ensure protection of the cell, and potentially to limit cross-talk between toxin–antitoxin pairs of the same family of TA systems. Further, there is a redundant use of toxin folds for different cellular targets and complexation with different classes of antitoxins, increasing the apparent requirement for the insulation of interactions. The presence of Type II TA systems has remained enigmatic with respect to potential benefits imparted to the host cells. In some cases, they play clear roles in survival associated with unfavorable growth conditions. More generally, they can also serve as a “cure” against acquisition of highly similar TA systems such as those found on plasmids or invading genetic elements that frequently carry virulence and resistance genes. The latter model is predicated on the ability of these highly specific cognate antitoxin–toxin interactions to form cross-reactions between chromosomal antitoxins and invading toxins. This review summarizes advances in the Type II TA system models with an emphasis on antitoxin cross-reactivity, including with invading genetic elements and cases where toxin proteins share a common fold yet interact with different families of antitoxins.

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Section: Interactions With Cognate Antitoxinssupporting

confidence: 88%

Section: Interactions With Cognate Antitoxinsmentioning

confidence: 99%

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Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems

Holt

Ruan

2020

Toxins

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“…VapBC family is the most abundant family of Type II TA systems in M. tuberculosis and its genome encodes for approximately 50 VapBC homologs (Ramage et al, 2009;Tandon et al, 2019b). VapC toxins inhibit mycobacterial growth by cleaving either mRNA, rRNA, or tRNA and their activity is neutralized by the levels of their cognate antitoxin (Winther et al, 2013;Cruz et al, 2015;Cintron et al, 2019).…”

Section: Overexpression Of Vapc21 Induces Bacteriostasis In M Smegmatismentioning

confidence: 99%

“…Here, we have performed a detailed functional and biochemical characterization of VapBC21 (Rv2757c-Rv2758c) TA system from M. tuberculosis. VapBC21 TA complex is absent in M. smegmatis but present in the genome sequences of members belonging to M. tuberculosis complex (Ramage et al, 2009;Tandon et al, 2019b). Although, the crystal structure of VapC21 is available, the cellular target for VapC21 is still unknown (Jardim et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis

et al. 2020

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The prokaryotic ubiquitous Toxin-antitoxin (TA) modules encodes for a stable toxin and an unstable antitoxin. VapBC subfamily is the most abundant Type II TA system in M. tuberculosis genome. However, the exact physiological role for most of these Type II TA systems are still unknown. Here, we have comprehensively characterized the VapBC21 TA locus from M. tuberculosis. The overexpression of VapC21 inhibited mycobacterial growth in a bacteriostatic manner and as expected, growth inhibition was abrogated upon co-expression of the cognate antitoxin, VapB21. We observed that the deletion of vapC21 had no noticeable influence on the in vitro and in vivo growth of M. tuberculosis. Using co-expression and biophysical studies, we observed that in addition to VapB21, VapC21 is also able to interact with non-cognate antitoxin, VapB32. The strength of interaction varied between the cognate and non-cognate TA pairs. The overexpression of VapC21 resulted in differential expression of approximately 435 transcripts in M. tuberculosis. The transcriptional profiles obtained upon ectopic expression of VapC21 was similar to those reported in M. tuberculosis upon exposure to stress conditions such as nutrient starvation and enduring hypoxic response. Further, VapC21 overexpression also led to increased expression of WhiB7 regulon and bacterial tolerance to aminoglycosides and ethambutol. Taken together, these results indicate that a complex network of interactions exists between non-cognate TA pairs and VapC21 contributes to drug tolerance in vitro.

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In memoriam of Narayanaswamy Srinivasan (1962–2021)

2021

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Bioinformatic and mutational studies of related toxin–antitoxin pairs in Mycobacterium tuberculosis predict and identify key functional residues

Cited by 26 publications

References 70 publications

Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems

Evaluating the Potential for Cross-Interactions of Antitoxins in Type II TA Systems

VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis

In memoriam of Narayanaswamy Srinivasan (1962–2021)

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