Regulated Proteolysis in Bacteria

Mahmoud, Samar A.; Chien, Peter

doi:10.1146/annurev-biochem-062917-012848

Cited by 153 publications

(146 citation statements)

References 111 publications

(126 reference statements)

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“…Proteases are proteolytic enzymes dedicated to regulated protein degradation. These enzymes play a decisive role in protein quality control and protein homeostasis in many bacteria, and thus are critical for normal cellular function and the adaptation of bacteria to diverse environments (Gur, Biran, & Ron, ; Mahmoud & Chien, ). One such protein is the ATP‐dependent Lon protease, which belongs to the AAA+ (ATPases associated with a variety of cellular activities) protein family.…”

Section: Introductionmentioning

confidence: 99%

The Lon‐2 protease of Borrelia burgdorferi is critical for infection in the mammalian host

Mason

Thompson

Ouyang

2020

Molecular Microbiology

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Borrelia burgdorferi encodes a functional homolog of canonical Lon protease termed Lon-2. To date, the contribution of Lon-2 to B. burgdorferi fitness and infection remains unexplored. Herein, we showed that expression of lon-2 was highly induced during animal infection, suggesting that Lon-2 is important for B. burgdorferi infection. We further generated a lon-2 deletion mutant. Compared with that of wild-type (WT) strain, the infectivity of the mutant was severely attenuated in a murine infection model. Although no growth defect was observed for the mutant in normal BSK-II medium, resistance of the lon-2 mutant to osmotic stress was markedly reduced. In addition, when exposed to tert-Butyl hydroperoxide, survival of the lon-2 mutant was impaired. In addition, we found that the protein levels of RpoS and RpoS-dependent OspC were decreased in the mutant. All these phenotypes were restored to WT or near-WT levels when lon-2 mutation was complemented in cis. Taken together, these results demonstrate that Lon-2 is critical for B. burgdorferi to establish infection and to cope with environmental stresses. This study provides a foundation for further uncovering the direct link between the dual roles of Lon-2 in protein quality control and bacterial pathogenesis.

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Section: Introductionmentioning

confidence: 99%

The Lon‐2 protease of Borrelia burgdorferi is critical for infection in the mammalian host

Mason

Thompson

Ouyang

2020

Molecular Microbiology

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“…ATP‐dependent Clp proteases are present in bacteria, as well as mitochondria and plastids (organelles of bacterial origin), where they regulate accumulation levels of a broad range of substrates (Alexopoulos, Guarne, & Ortega, ; Liu, Ologbenla, & Houry, ; Nishimura, Kato, & Sakamoto, ; Nishimura & van Wijk, ; Sauer & Baker, ). The first step in the CLP degradation process requires the recognition of substrates by the CLP AAA+ chaperones, possibly aided by specific adaptors (also named recognins) that recognize and deliver specific substrates (Kuhlmann & Chien, ; Mahmoud & Chien, ). The ATP‐dependent CLP chaperones then dock onto CLP protease core complexes consisting of two stacked heptameric rings, and unfold and direct substrates into the CLP protease complex (Olivares, Baker, & Sauer, ).…”

Section: Introductionmentioning

confidence: 99%

Consequences of the loss of catalytic triads in chloroplast CLPPR protease core complexes in vivo

et al. 2018

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The essential chloroplast CLP protease system consists of a tetradecameric proteolytic core with catalytic P (P1, 3–6) and non‐catalytic R (R1–4) subunits, CLP chaperones and adaptors. The chloroplast CLP complex has a total of ten catalytic sites,but it is not known how many of these catalytic sites can be inactivated before plants lose viability. Here we show that CLPP3 and the catalytically inactive variant CLPP3S164A fully complement the developmental arrest of the clpp3‐1 null mutant, even under environmental stress. In contrast, whereas the inactive variant CLPP5S193A assembled into the CLP core, it cannot rescue the embryo lethal phenotype of the clpp5‐1 null mutant. This shows that CLPP3 makes a unique structural contribution but its catalytic site is dispensable, whereas the catalytic activity of CLPP5 is essential. Mass spectrometry of affinity‐purified CLP cores of the complemented lines showed highly enriched CLP cores. Other chloroplast proteins were co‐purified with the CLP cores and are candidate substrates. A strong overlap of co‐purified proteins between the CLP core complexes with active and inactive subunits indicates that CLP cores with reduced number of catalytic sites do not over‐accumulate substrates, suggesting that the bottle‐neck for degradation is likely substrate recognition and unfolding by CLP adaptors and chaperones, upstream of the CLP core.

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“…However, we found no evidence that either ppGpp or polyphosphate are required for the increased degradation of antitoxins in stressful growth conditions. An alternative possibility is that because Lon normally degrades misfolded proteins that arise during translation (Mahmoud and Chien, 2018;Van Melderen and Aertsen, 2009), whenever the abundance of misfolded or incompletely synthesized peptides is substantially reduced, Lon may be more accessible to lower affinity substrates, such as antitoxins. The relatively long half-life of many antitoxins (>20 min) compared to some other Lon substrates (e.g.…”

Section: Stress-induced Changes In Antitoxin Degradationmentioning

confidence: 99%

Stress induces the transcription of toxin-antitoxin systems but does not activate toxin

LeRoux

Culviner

Liu

et al. 2020

Preprint

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Toxin-antitoxin (TA) systems are ubiquitous genetic elements in bacterial genomes, but their functions are controversial. Although they are frequently postulated to regulate cell growth following stress, few null phenotypes for TA systems have been reported. Here, we show that TA transcript levels can increase substantially in response to stress, but toxin is not liberated. We find that the growth of an Escherichia coli strain lacking 10 TA systems encoding endoribonuclease toxins is not affected following exposure to six stresses that each trigger TA transcription.Additionally, using RNA-sequencing, we find no evidence of mRNA cleavage following stress.Stress-induced transcription arises from antitoxin degradation and relief of transcriptional autoregulation. Importantly, although free antitoxin is readily degraded in vivo, antitoxin bound to toxin is protected from proteolysis, preventing release of active toxin. Thus, transcription is not a reliable marker of TA activity, and TA systems likely do not strongly promote survival following stress.

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Regulated Proteolysis in Bacteria

Cited by 153 publications

References 111 publications

The Lon‐2 protease of Borrelia burgdorferi is critical for infection in the mammalian host

The Lon‐2 protease of Borrelia burgdorferi is critical for infection in the mammalian host

Consequences of the loss of catalytic triads in chloroplast CLPPR protease core complexes in vivo

Stress induces the transcription of toxin-antitoxin systems but does not activate toxin

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