Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

Luo, Weiwei; Shu, Hong‐Bing

doi:10.1002/1873-3468.12796

Cited by 12 publications

(7 citation statements)

References 58 publications

(137 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…g ., Caulobacter crescentus DivL [65] or Streptococcus pyogenes RocA [66]] and eukaryotes [60–63] where they often regulate their cognate protease / kinase. Pseudoproteases, however, have mostly been studied in eukaryotes [64]. Prior work by Hershey and colleagues [67] has revealed that Magnetospirillum magneticum uses a pseudoprotease, MamO, to bind metals for magnetosome development.…”

Section: Discussionmentioning

confidence: 99%

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The requirement for co-germinants during Clostridium difficile spore germination is influenced by mutations in yabG and cspA

2019

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Clostridium difficile spore germination is critical for the transmission of disease. C . difficile spores germinate in response to cholic acid derivatives, such as taurocholate (TA), and amino acids, such as glycine or alanine. Although the receptor with which bile acids are recognized (germinant receptor) is known, the amino acid co-germinant receptor has remained elusive. Here, we used EMS mutagenesis to generate mutants with altered requirements for the amino acid co-germinant, similar to the strategy we used previously to identify the bile acid germinant receptor, CspC. Surprisingly, we identified strains that do not require co-germinants, and the mutant spores germinated in response to TA alone. Upon sequencing these mutants, we identified different mutations in yabG . In C . difficile , yabG expression is required for the processing of key germination components to their mature forms ( e . g ., CspBA to CspB and CspA). A defined yabG mutant exacerbated the EMS mutant phenotype. Building upon this work, we found that small deletions in cspA resulted in spores that germinated in the presence of TA alone without the requirement of a co-germinant. cspA encodes a pseudoprotease that was previously shown to be important for incorporation of the CspC germinant receptor. Herein, our study builds upon the role of CspA during C . difficile spore germination by providing evidence that CspA is important for recognition of co-germinants during C . difficile spore germination. Our work suggests that two pseudoproteases (CspC and CspA) likely function as the C . difficile germinant receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The requirement for co-germinants during Clostridium difficile spore germination is influenced by mutations in yabG and cspA

2019

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“…Despite the loss of their characteristic enzymatic activity, pseudoenzymes have emerged as important proteins that act as allosteric regulators of active enzymes 22 , signal integrators 23,24 and as regulators of protein trafficking 25 . Most biochemical studies of pseudoenzymes have been carried out in Drosophila or mammals 26–28 . In this study, we characterized a novel pseudo-aspartic peptidase from the tick R .…”

Section: Introductionmentioning

confidence: 99%

Novel pseudo-aspartic peptidase from the midgut of the tick Rhipicephalus microplus

Parizi

Torquato

et al. 2019

Sci Rep

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The characterization of Rhipicephalus microplus tick physiology can support efforts to develop and improve the efficiency of control methods. A sequence containing a domain with similarity to one derived from the aspartic peptidase family was isolated from the midgut of engorged female R. microplus. The lack of the second catalytic aspartic acid residue suggest that it may be a pseudo-aspartic peptidase, and it was named RmPAP. In this work we confirm the lack of proteolytic activity of RmPAP and investigate it’s non-proteolytic interaction with bovine hemoglobin by Surface Plasmon Resonance and phage display. Moreover we carried out RNAi interference and artificial feeding of ticks with anti-RmPAP antibodies to assess it’s possible biological role, although no changes were observed in the biological parameters evaluated. Overall, we hypothesize that RmPAP may act as a carrier of hemoglobin/heme between the tick midgut and the ovaries.

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“…We hypothesize that CspC (functioning as the bile acid germinant receptor) and CspA (functioning as the amino acid co-germinant receptor) inhibit CspB activity within dormant spores (Figure 8). These two pseudoproteases would regulate the activity of CspB so that it does not prematurely activate proSleC, potentially similar to how other pseudoproteases / pseudokinases regulate activity of their cognate proteins [55–59]. Because yabG mutant spores package full length CspBA, where CspA is tethered to CspB, CspC alone prevents CspB from cleaving proSleC into its active form, and TA might dislodge CspC from CspB (this is consistent with our prior publication that indicates that CspC may have an inhibitory activity during spore germination [33]).…”

Section: Discussionmentioning

confidence: 99%

The requirement for the amino acid co-germinant duringC. difficilespore germination is influenced by mutations inyabGandcspA

Shrestha

Sorg

2018

Preprint

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13Clostridium difficile spore germination is critical for the transmission of disease. C. difficile 14 spores germinate in response to cholic acid derivatives, such as taurocholate (TA), and amino 15 acids, such as glycine or alanine. Although the bile acid germinant receptor is known, the amino 16 acid germinant receptor has remained elusive. Here, we used EMS mutagenesis to generate 17 mutants with altered requirements for the amino acid co-germinant, similar to the strategy used 18 previously to identify the bile acid receptor, CspC. Surprisingly, we identified strains that do not 19 require amino acids as co-germinants, and the mutant spores germinated in response to TA alone. 20 Upon sequencing these mutants, we identified different mutations in yabG. In C. difficile, yabG 21 expression is required for the processing of CspBA to CspB and CspA and preproSleC to 22 proSleC during spore formation. A defined yabG mutant exacerbated the EMS mutant 23 phenotype. Moreover, we found that various mutations in cspA caused spores to germinate in the 24 presence of TA alone without the requirement of an amino acid. Thus, our study provides 25 evidence that apart from regulating the CspC levels in the spore, CspA is important for 26 recognition of amino acids as co-germinants during C. difficile spore germination and that two 27 pseudoproteases (CspC and CspA) function as the C. difficile germinant receptors.28 86 inhibitory pro-peptide from proSleC, a spore cortex hydrolase that degrades the cortex 87 peptidoglycan, thereby activating the protein [38][39][40][41]. In C. difficile, CspB and CspA are encoded 88 by one ORF and the resulting protein is post-translationally processed into CspB and CspA and 89 then further processed by the sporulation specific protease, YabG [14,[42][43][44]. CspC is encoded 90 downstream of cspBA and is part of the same transcriptional unit. Interestingly, the catalytic 91 residues in CspA and CspC are lost, suggesting that only the CspB protein can process proSleC 92 to its active, cortex degrading form [37, 44]. Although present in the spore, and essential for C. 93 difficile spore germination, the CspA pseudoprotease has only been shown to regulate the 94 incorporation of CspC into the spore [42, 43]. 95In our working model for spore germination, activation of CspC by TA leads to the 96 activation of the CspB protein which cleaves proSleC into its active form. Activated SleC 97 degrades cortex and the core releases CaDPA in exchange for water by a mechanosensing 98 mechanism [45]. Because the receptor with which amino acids interact is unknown, we sought to 99 screen for chemically-generated mutants that have altered amino acid requirements during spore 100 germination [similar to the strategy used to identify the bile acid germinant receptor [37]]. Here, 101 we report that a mutation in yabG gene results in strains whose spores no longer respond to or 102 require amino acid co-germinants but respond to TA alone as a spore germinant. We hypothesize 103 that the misprocessing o...

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Emerging roles of rhomboid‐like pseudoproteases in inflammatory and innate immune responses

Cited by 12 publications

References 58 publications

The requirement for co-germinants during Clostridium difficile spore germination is influenced by mutations in yabG and cspA

The requirement for co-germinants during Clostridium difficile spore germination is influenced by mutations in yabG and cspA

Novel pseudo-aspartic peptidase from the midgut of the tick Rhipicephalus microplus

The requirement for the amino acid co-germinant duringC. difficilespore germination is influenced by mutations inyabGandcspA

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