Strain-Dependent Recognition of a Unique Degradation Motif by ClpXP in Streptococcus mutans

Jana, Biswanath; Tao, Liang; Biswas, Indranil

doi:10.1128/msphere.00287-16

Cited by 17 publications

(25 citation statements)

References 50 publications

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“…Theoretically, with the deficiency of MecA, the ClpC/P proteolysis machinery fails to function properly, which leads to disturbance of cellular functions contributing to the altered cell morphology, the defects in cell division and the reduced cell envelope stress and other related phenotypes. On the other hand, recent studies have also shown that the ClpP protease in S. mutans affects stress tolerance responses and biofilm formation and regulates large groups of genes including those related to biofilm formation ( Lemos and Burne, 2002 ; Kajfasz et al, 2009 , 2011 ; Chattoraj et al, 2010 ; Tao and Biswas, 2015 ; Jana et al, 2016 ). However, none of the Clp mutants display any phenotypes featured with the MecA-deficient mutants ( Lemos and Burne, 2002 ; Kajfasz et al, 2009 ; Chattoraj et al, 2010 ; Kajfasz et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Deficiency of MecA in Streptococcus mutans Causes Major Defects in Cell Envelope Biogenesis, Cell Division, and Biofilm Formation

Jorgensen

Beatty

et al. 2018

Front. Microbiol.

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MecA is an adaptor protein that guides the ClpC/P-mediated proteolysis. A S. mutans MecA-deficient mutant was constructed by double-crossover allelic exchange and analyzed for the effects of such a deficiency on cell biology and biofilm formation. Unlike the wild-type, UA159, the mecA mutant, TW416, formed mucoid and smooth colonies, severely clumped in broth and had a reduced growth rate. Transmission electron microscopy analysis revealed that TW416 grows primarily in chains of giant “swollen” cells with multiple asymmetric septa, unlike the coccoid form of UA159. As compared to UA159, biofilm formation by TW416 was significantly reduced regardless of the carbohydrate sources used for growth (P < 0.001). Western blot analysis of TW416 whole cell lysates showed a reduced expression of the glucosyltransferase GtfC and GtfB, as well as the P1 and WapA adhesins providing an explanation for the defective biofilm formation of TW416. When analyzed by a colorimetric assay, the cell wall phosphate of the mutant murein sacculi was almost 20-fold lower than the parent strain (P < 0.001). Interestingly, however, when analyzed using immunoblotting of the murein sacculi preps with UA159 whole cell antiserum as a probe, TW416 was shown to possess significantly higher signal intensity as compared to the wild-type. There is also evidence that MecA in S. mutans is more than an adaptor protein, although how it modulates the bacterial pathophysiology, including cell envelope biogenesis, cell division, and biofilm formation awaits further investigation.

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Section: Discussionmentioning

confidence: 99%

Deficiency of MecA in Streptococcus mutans Causes Major Defects in Cell Envelope Biogenesis, Cell Division, and Biofilm Formation

Jorgensen

Beatty

et al. 2018

Front. Microbiol.

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“…While this is somewhat surprising, we previously noticed that different S. mutans strains behave differently. For example, we reported that the ClpX/P protease complex recognizes substrates with the C-terminal LPF motif in certain S. mutans strains but not all, despite the fact that all strains contain functional ClpX/P [52]. We believe that an unknown activator is responsible for the observed PclpP induction and it is a substrate of ClpE/P.…”

Section: Discussionmentioning

confidence: 96%

Induction of clpP expression by cell-wall targeting antibiotics in Streptococcus mutans

Khara

Biswas

2020

Microbiology

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Streptococcus mutans is one of the major bacteria of the human oral cavity that is associated with dental caries. The pathogenicity of this bacterium is attributed to its ability to rapidly respond and adapt to the ever-changing conditions of the oral cavity. The major player in this adaptive response is ClpP, an intracellular protease involved in degradation of misfolded proteins during stress responses. S. mutans encodes a single clpP gene with an upstream region uniquely containing multiple tandem repeat sequences (RSs). Here, we explored expression of clpP with respect to various stresses and report some new findings. First, we found that at sub-inhibitory concentration, certain cell-wall damaging antibiotics were able to induce clpP expression. Specifically, third- and fourth-generation cephalosporins that target penicillin-binding protein 3 (PBP3) strongly enhanced the clpP expression. However, induction of clpP was weak when the first-generation cephalosporins with lower affinity to PBP3 were used. Surprisingly, carbapenems, which primarily target PBP2, induced expression of clpP the least. Second, we found that a single RS element was capable of inducing clpP expression as efficiently as with the wild-type seven RS elements. Third, we found that the RS-element-mediated modulation of clpP expression was strain dependent, suggesting that specific host factors might be involved in the transcription. And finally, we observed that ClpP regulates its own expression, as the expression of clpP-gusA was higher in a clpP-deficient mutant. This suggests that ClpP is involved in the degradation of activator(s) involved in its own transcription.

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“…The quantitative proteomic dataset from the ΔclpQ mutant also shows a large significant increase in DivIVA suggesting it may be a direct target of the ClpYQ protease. Intriguingly DivIVA is proposed to be a substrate of ClpXP in Streptococcus mutans, which lacks clpQ 73 . It is thus possible that ClpXP plays a minor role in degrading DivIVA in B. subtilis, supported by the increase in DivIVA abundance in two out of three replicates of the ΔclpP mutant dataset.…”

Section: Aaa+ Proteases Clpyq and Clpxp Are Targets Of Armeniaspirolmentioning

confidence: 99%

Armeniaspirols inhibit the AAA+ proteases ClpXP and ClpYQ leading to cell division arrest in Gram-positive bacteria

Labana

Dornan

Lafreniere

et al. 2019

Preprint

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The emergence of multi-drug resistant organisms clinically presents major challenges to managing human health and threaten the great progress that has been made in preventing morbidity in the age of antibiotics. In order to combat these pathogens, new antibiotics with diverse mechanisms of action will be required. Armeniaspirols represent a novel class of natural product-based antibiotic molecules with unknown mechanisms of action. Herein, we synthesized analogs of armeniaspirol and studied their antibiotic properties and mechanism of action. Using a combination of chemoproteomics, quantitative proteomics, and a battery of functional assays we discovered that armeniaspirols inhibit the bacterial divisome through direct inhibition of the ClpYQ and ClpXP proteases. This was validated by comparisons with genetic knockouts. Sub-lethal challenges suggested that resistance to armeniaspirol inhibition of ClpYQ and ClpXP proteases was difficult to achieve without catastrophic consequences for the bacteria. Thus, the armeniaspirols represent an important new tool to combat multi-drug resistance, through a potent and highly novel mechanism of action.

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Strain-Dependent Recognition of a Unique Degradation Motif by ClpXP in Streptococcus mutans

Cited by 17 publications

References 50 publications

Deficiency of MecA in Streptococcus mutans Causes Major Defects in Cell Envelope Biogenesis, Cell Division, and Biofilm Formation

Deficiency of MecA in Streptococcus mutans Causes Major Defects in Cell Envelope Biogenesis, Cell Division, and Biofilm Formation

Induction of clpP expression by cell-wall targeting antibiotics in Streptococcus mutans

Armeniaspirols inhibit the AAA+ proteases ClpXP and ClpYQ leading to cell division arrest in Gram-positive bacteria

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