The mycobacterial PhoH2 proteins are type II toxin antitoxins coupled to RNA helicase domains

Andrews, Emma S.V.; Arcus, Vickery L.

doi:10.1016/j.tube.2015.03.013

Cited by 23 publications

(41 citation statements)

References 49 publications

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“…These PIN domains function as sequence specific single stranded RNases [46]. Recently, a PIN-PhoH protein was found to be the RNase toxin in a toxin-antitoxin system from Myocbacterium tuberculosis [23]. Thus, the PIN-PhoH protein in Synechococcus WH8102 may limit phage progeny production by acting as an RNase toxin which uses the energy provided from the hydrolysis of ATP by the PhoH ATPase domain to cleave phage RNA during infection.…”

Section: Discussionmentioning

confidence: 99%

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Two Synechococcus genes, Two Different Effects on Cyanophage Infection

Fedida

Lindell

2017

Viruses

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Synechococcus is an abundant marine cyanobacterium that significantly contributes to primary production. Lytic phages are thought to have a major impact on cyanobacterial population dynamics and evolution. Previously, an investigation of the transcriptional response of three Synechococcus strains to infection by the T4-like cyanomyovirus, Syn9, revealed that while the transcript levels of the vast majority of host genes declined soon after infection, those for some genes increased or remained stable. In order to assess the role of two such host-response genes during infection, we inactivated them in Synechococcus sp. strain WH8102. One gene, SYNW1659, encodes a domain of unknown function (DUF3387) that is associated with restriction enzymes. The second gene, SYNW1946, encodes a PIN-PhoH protein, of which the PIN domain is common in bacterial toxin-antitoxin systems. Neither of the inactivation mutations impacted host growth or the length of the Syn9 lytic cycle. However, the DUF3387 mutant supported significantly lower phage DNA replication and yield of phage progeny than the wild-type, suggesting that the product of this host gene aids phage production. The PIN-PhoH mutant, on the other hand, allowed for significantly higher Syn9 genomic DNA replication and progeny production, suggesting that this host gene plays a role in restraining the infection process. Our findings indicate that host-response genes play a functional role during infection and suggest that some function in an attempt at defense against the phage, while others are exploited by the phage for improved infection.

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Section: Discussionmentioning

confidence: 99%

“…The second two-gene operon may form a toxin-antitoxin module [22,23], which is also a known anti-phage defense mechanism [21,24,25]. The first gene in the operon, SYNW1946, contains a single-stranded RNA nuclease PIN domain [16], which is commonly found in toxins from bacterial toxin-antitoxin operons [22].…”

Section: Introductionmentioning

confidence: 99%

Two Synechococcus genes, Two Different Effects on Cyanophage Infection

Fedida

Lindell

2017

Viruses

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“…PhoH shows ATP-binding activity and may be an ATPase. Moreover, when fused to a PilT N-terminal domain in PhoH2 proteins, it possesses ATPase and RNA helicase activity (33,36). Thus, PhoH proteins seem to be very versatile, and their ATPase activity may have been recruited to provide energy in various processes.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial Peptide Resistance Genes in the Plant Pathogen Dickeya dadantii

Pandin

Caroff

Condemine

2016

Appl Environ Microbiol

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Modification of teichoic acid through the incorporation of D-alanine confers resistance in Gram-positive bacteria to antimicrobial peptides (AMPs). This process involves the products of the dltXABCD genes. These genes are widespread in Gram-positive bacteria, and they are also found in a few Gram-negative bacteria. Notably, these genes are present in all soft-rot enterobacteria (Pectobacterium and Dickeya) whose dltDXBAC operons have been sequenced. We studied the function and regulation of these genes in Dickeya dadantii. dltB expression was induced in the presence of the AMP polymyxin. It was not regulated by PhoP, which controls the expression of some genes involved in AMP resistance, but was regulated by ArcA, which has been identified as an activator of genes involved in AMP resistance. However, arcA was not the regulator responsible for polymyxin induction of these genes in this bacterium, which underlines the complexity of the mechanisms controlling AMP resistance in D. dadantii. Two other genes involved in resistance to AMPs have also been characterized, phoS and phoH. dltB, phoS, phoH, and arcA but not dltD mutants were more sensitive to polymyxin than the wild-type strain. Decreased fitness of the dltB, phoS, and phoH mutants in chicory leaves indicates that their products are important for resistance to plant AMPs. IMPORTANCE Gram-negative bacteria can modify their lipopolysaccharides (LPSs) to resist antimicrobial peptides (AMPs). Soft-rot enterobacteria (Dickeya and Pectobacterium spp.) possess homologues of the dlt genes in their genomes which, in Gram-positive bacteria, are involved in resistance to AMPs. In this study, we show that these genes confer resistance to AMPs, probably by modifying LPSs, and that they are required for the fitness of the bacteria during plant infection. Two other new genes involved in resistance were also analyzed. These results show that bacterial resistance to AMPs can occur in bacteria through many different mechanisms that need to be characterized.

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“…Experimental investigations of PhoH2 proteins have primarily focused on those from mycobacteria. In Mycobacterium tuberculosis and Mycobacterium smegmatis , PhoH2 has sequence‐specific RNA and ATP‐dependent unwinding activity coupled with degradation of the single‐stranded RNA (ssRNA) product . PhoH2 is specific for the terminal combination of RNA bases a 5′—A C [A/U] [A/U] [G/C]—3′ overhang, suggesting a precise target site.…”

Section: Phoh2 Proteins (Pin‐phoh)mentioning

confidence: 99%

“…In the genomes of Mycobacterium ulcerans , Mycobacterium marinum , and Mycobacterium kansasii , phoAT is annotated as an ORF and in addition to work by us, phoAT has been identified in M. tuberculosis transcriptome studies . In more distantly related mycobacteria, PhoAT shares less sequence identity (47% in M. smegmatis ) (Figure 2b) but nonetheless interacts with its cognate PhoH2 protein . The PhoAT‐PhoH2 complex appears to be an adaptation of a Type II toxin–antitoxin system in which the PIN‐domain ribonuclease is now fused with an RNA helicase.…”

Section: Phoh2 Proteins (Pin‐phoh)mentioning

confidence: 99%

PhoH2 proteins couple RNA helicase and RNAse activities

Andrews

Arcus

2020

Protein Science

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PhoH2 proteins are found in a very diverse range of microorganisms that span bacteria and archaea. These proteins are composed of two domains: an N‐terminal PIN‐domain fused with a C‐terminal PhoH domain. Collectively this fusion functions as an RNA helicase and ribonuclease. In other genomic contexts, PINdomains and PhoHdomains are separate but adjacent suggesting association to achieve similar function. Exclusively among the mycobacteria, PhoH2 proteins are encoded in the genome with an upstream gene, phoAT, which is thought to play the role of an antitoxin (in place of the traditional VapB antitoxin that lies upstream of the 47 other PINdomains in the mycobacterial genome). This review examines PhoH2 proteins as a whole and describes the bioinformatics, biochemical, structural, and biological properties of the two domains that make up PhoH2: PIN and PhoH. We review the transcriptional regulators of phoH2 from two mycobacterial species and speculate on the function of PhoH2 proteins in the context of a Type II toxin–antitoxin system which are thought to play a role in the stress response in bacteria.

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The mycobacterial PhoH2 proteins are type II toxin antitoxins coupled to RNA helicase domains

Cited by 23 publications

References 49 publications

Two Synechococcus genes, Two Different Effects on Cyanophage Infection

Two Synechococcus genes, Two Different Effects on Cyanophage Infection

Antimicrobial Peptide Resistance Genes in the Plant Pathogen Dickeya dadantii

PhoH2 proteins couple RNA helicase and RNAse activities

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