RelE, a global inhibitor of translation, is activated during nutritional stress

Christensen, Susanne K.; Mikkelsen, Marie; Pedersen, Kim Brint; Gerdes, Kenn

doi:10.1073/pnas.251327898

Cited by 411 publications

(566 citation statements)

References 36 publications

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“…Lon is also involved in the turnover of several antitoxin proteins in toxin-antitoxin systems (Gerdes, 2000). For example, Lon degrades RelB, leading to the accumulation of RelE toxin and to global inhibition of translation (Christensen et al, 2001). It has been suggested that this action does not kill cells, but enables them to enter a reversible "bacteriostatic" state (Pedersen et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Lon protease promotes survival of Escherichia coli during anaerobic glucose starvation

Luo¹,

McNeill²,

Myers³

et al. 2007

Arch Microbiol

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In Escherichia coli, Lon is an ATP-dependent protease which degrades misfolded proteins and certain rapidly-degraded regulatory proteins. Given that oxidatively damaged proteins are generally degraded rather than repaired, we anticipated that Lon deficient cells would exhibit decreased viability during aerobic, but not anaerobic, carbon starvation. We found that the opposite actually occurs. Wild-type and Lon deficient cells survived equally well under aerobic conditions, but Lon deficient cells died more rapidly than the wild-type under anaerobiosis. Aerobic induction of the Clp family of ATP-dependent proteases could explain these results, but direct quantitation of Clp protein established that its level was not affected by Lon deficiency and overexpression of Clp did not rescue the cells under anaerobic conditions. We conclude that the Lon protease supports survival during anaerobic carbon starvation by a mechanism which does not depend on Clp.

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Section: Introductionmentioning

confidence: 99%

Lon protease promotes survival of Escherichia coli during anaerobic glucose starvation

Luo¹,

McNeill²,

Myers³

et al. 2007

Arch Microbiol

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“…Even though the antitoxin is labile, its rate of synthesis is sufficiently high to generate a steady-state level of antitoxin that is higher than that of the toxin in exponentially growing cells. However, in starved or otherwise slow-growing cells, protease-mediated degradation of antitoxin may lead to toxin activation and inhibition of translation 7 .…”

mentioning

confidence: 99%

VapC20 of Mycobacterium tuberculosis cleaves the Sarcin–Ricin loop of 23S rRNA

et al. 2013

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The highly persistent and often lethal human pathogen, Mycobacterium tuberculosis contains at least 88 toxin-antitoxin genes. More than half of these encode VapC PIN domain endoribonucleases that inhibit cell growth by unknown mechanisms. Here we show that VapC20 of M. tuberculosis inhibits translation by cleavage of the Sarcin-Ricin loop (SRL) of 23S ribosomal RNA at the same position where Sarcin and other eukaryotic ribotoxins cleave. Toxin-inhibited cells can be rescued by the expression of the antitoxin, thereby raising the possibility that vapC20 contributes to the extreme persistence exhibited by M. tuberculosis. VapC20 cleavage is inhibited by mutations in the SRL that flank the cleavage site but not by changes elsewhere in the loop. Disruption of the SRL stem abolishes cleavage; however, further mutations that restore the SRL stem structure restore cleavage, revealing that the structure rather than the exact sequence of the SRL is important for this activity.

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“…One possibility is that the slowly processed, inactive full-length hokB mRNA functions as a reservoir that does not require de novo RNA synthesis to become translationally active at the onset of sudden starvation because slow processing of the already-present full-length mRNA leads to formation of the truncated, active HokB mRNA while SokB-RNA is simultaneously depleted by RNase E (figure 4). Similar considerations apply to type II TA loci in which the TA complexes may function as reservoirs from which the toxins can be activated without the requirement for de novo protein synthesis [31]. …”

Section: Hypothesis: Rnase E Controls Sokb-rna Levelmentioning

confidence: 97%

“…Lon protease degrades RelB antitoxin [31]. (b) Confirmed type I (red) and type II (blue) TA modules encoded by the chromosome of E. coli K-12.…”

Section: Control Of Persistence By Type II Toxinantitoxin Modulesmentioning

confidence: 99%

Hypothesis: type I toxin–antitoxin genes enter the persistence field—a feedback mechanism explaining membrane homoeostasis

Gerdes

2016

Phil. Trans. R. Soc. B

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Bacteria form persisters, cells that are tolerant to multiple antibiotics and other types of environmental stress. Persister formation can be induced either stochastically in single cells of a growing bacterial ensemble, or by environmental stresses, such as nutrient starvation, in a subpopulation of cells. In many cases, the molecular mechanisms underlying persistence are still unknown. However, there is growing evidence that, in enterobacteria, both stochastically and environmentally induced persistence are controlled by the second messenger (p)ppGpp. For example, the ‘alarmone’ (p)ppGpp activates Lon, which, in turn, activates type II toxin–antitoxin (TA) modules to thereby induce persistence. Recently, it has been shown that a type I TA module, hokB / sokB , also can induce persistence. In this case, the underlying mechanism depends on the universally conserved GTPase Obg and, surprisingly, also (p)ppGpp. In the presence of (p)ppGpp, Obg stimulates hokB transcription and induces persistence. HokB toxin expression is under both negative and positive control: SokB antisense RNA inhibits hokB mRNA translation, while (p)ppGpp and Obg together stimulate hokB transcription. HokB is a small toxic membrane protein that, when produced in modest amounts, leads to membrane depolarization, cell stasis and persistence. By contrast, overexpression of HokB disrupts the membrane potential and kills the cell. These observations raise the question of how expression of HokB is regulated. Here, I propose a homoeostatic control mechanism that couples HokB expression to the membrane-bound RNase E that degrades and inactivates SokB antisense RNA. This article is part of the themed issue ‘The new bacteriology’.

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RelE, a global inhibitor of translation, is activated during nutritional stress

Cited by 411 publications

References 36 publications

Lon protease promotes survival of Escherichia coli during anaerobic glucose starvation

Lon protease promotes survival of Escherichia coli during anaerobic glucose starvation

VapC20 of Mycobacterium tuberculosis cleaves the Sarcin–Ricin loop of 23S rRNA

Hypothesis: type I toxin–antitoxin genes enter the persistence field—a feedback mechanism explaining membrane homoeostasis

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