Substrate Cleavage Profiling Suggests a Distinct Function of Bacteroides fragilis Metalloproteinases (Fragilysin and Metalloproteinase II) at the Microbiome-Inflammation-Cancer Interface

Shiryaev, Sergey A.; Remacle, Albert G.; Chernov, Andrei V.; Golubkov, Vladislav S.; Motamedchaboki, Khatereh; Muranaka, Norihito; Dambacher, Corey M.; Čapek, Petr; Kukreja, Muskan; Kozlov, I. A.; Perucho, Manuel; Cieplak, Piotr; Strongin, Alex Y.

doi:10.1074/jbc.m113.516153

Cited by 28 publications

(29 citation statements)

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“…The Arg–Ala scissile bond between the prodomain linker and the N‐end of the catalytic domain better matches the cleavage preferences of MPII than FRA3 (see below ‘Multiplex peptide cleavage assay’). These differences, especially when combined, explain a looser association of the prodomain with the catalytic domain in MPII relative to FRA3 and provide structural requirements for the efficient self‐activation of the MPII proenzyme . Thus, the recombinant MPII proenzyme self‐activates in the course of its purification from Escherichia coli cells.…”

Section: Resultsmentioning

confidence: 99%

“…By cleaving E‐cadherin, FRAs (either alone or in collaboration with other proteinases) ultimately weaken cell‐to‐cell contacts, enabling B. fragilis to penetrate the intestinal epithelium, where the bacterium's polysaccharide capsule causes abscesses and inflammation within the tissue. The structural–functional characteristics of MPII, by contrast, are barely known . This information would aid in the identification of cleavage targets, thus helping to decipher the molecular effects of MPII and FRA proteolysis on host cells.…”

Section: Introductionmentioning

confidence: 99%

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Structural and functional diversity of metalloproteinases encoded by the Bacteroides fragilis pathogenicity island

et al. 2014

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Summary Bacteroides fragilis causes the majority of anaerobic infections in humans. The presence of a pathogenicity island in the genome discriminates pathogenic and commensal B. fragilis strains. The island encodes metalloproteinase II (MPII), a potential virulence protein, and one of three homologous fragilysin isozymes (FRA; also termed B. fragilis toxin or BFT). Here, we report biochemical data on the structural-functional characteristics of the B. fragilis pathogenicity island proteases by reporting the crystal structure of MPII at 2.13 Å resolution combined with detailed characterization of the cleavage preferences of MPII and FRA3 (as a representative of the FRA isoforms) identified using a high-throughput peptide cleavage assay with 18,583 substrate peptides. We suggest that the evolution of the MPII catalytic domain can be traced to human and archaebacterial proteinases, while the prodomain fold is a feature specific to MPII and FRA. We conclude that the catalytic domain of both MPII and FRA3 evolved differently relative to the prodomain, and that the prodomain evolved specifically to fit the B. fragilis pathogenicity. Overall, our data provide insights into the evolution of cleavage specificity and activation mechanisms in the virulent metalloproteinases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural and functional diversity of metalloproteinases encoded by the Bacteroides fragilis pathogenicity island

et al. 2014

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“…Bacterial endotoxins, metabolic byproducts of bacterial infection, and increased enzymatic activity as a result of bacterial infection, can induce somatic mutations and signaling pathway alterations [58]. Furthermore, the inflammatory cells and cytokines found in the tumor microenvironment of bacterial related chronic inflammation can lead to the creation of reactive oxygen and nitrogen species, which can also induce DNA alterations [24, 59, 60]. …”

Section: Discussionmentioning

confidence: 99%

16S rRNA amplicon sequencing identifies microbiota associated with oral cancer, human papilloma virus infection and surgical treatment

et al. 2016

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Systemic inflammatory events and localized disease, mediated by the microbiome, may be measured in saliva as head and neck squamous cell carcinoma (HNSCC) diagnostic and prognostic biomonitors. We used a 16S rRNA V3-V5 marker gene approach to compare the saliva microbiome in DNA isolated from Oropharyngeal (OPSCC), Oral Cavity Squamous Cell Carcinoma (OCSCC) patients and normal epithelium controls, to characterize the HNSCC saliva microbiota and examine their abundance before and after surgical resection.The analyses identified a predominance of Firmicutes, Proteobacteria and Bacteroidetes, with less frequent presence of Actinobacteria and Fusobacteria before surgery. At lower taxonomic levels, the most abundant genera were Streptococcus, Prevotella, Haemophilus, Lactobacillus and Veillonella, with lower numbers of Citrobacter and Neisseraceae genus Kingella. HNSCC patients had a significant loss in richness and diversity of microbiota species (p<0.05) compared to the controls. Overall, the Operational Taxonomic Units network shows that the relative abundance of OTU's within genus Streptococcus, Dialister, and Veillonella can be used to discriminate tumor from control samples (p<0.05). Tumor samples lost Neisseria, Aggregatibacter (Proteobacteria), Haemophillus (Firmicutes) and Leptotrichia (Fusobacteria). Paired taxa within family Enterobacteriaceae, together with genus Oribacterium, distinguish OCSCC samples from OPSCC and normal samples (p<0.05). Similarly, only HPV positive samples have an abundance of genus Gemellaceae and Leuconostoc (p<0.05). Longitudinal analyses of samples taken before and after surgery, revealed a reduction in the alpha diversity measure after surgery, together with an increase of this measure in patients that recurred (p<0.05). These results suggest that microbiota may be used as HNSCC diagnostic and prognostic biomonitors.

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Section: Discussionmentioning

confidence: 99%

16S rRNA amplicon sequencing identifies microbiota associated with oral cancer, Human Papilloma Virus infection and surgical treatment

et al. 2016

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Systemic inflammatory events and localized disease, mediated by the microbiome, may be measured in saliva as head and neck squamous cell carcinoma (HNSCC) diagnostic and prognostic biomonitors. We used a 16S rRNA V3-V5 marker gene approach to compare the saliva microbiome in DNA isolated from Oropharyngeal (OPSCC), Oral Cavity Squamous Cell Carcinoma (OCSCC) patients and normal epithelium controls, to characterize the HNSCC saliva microbiota and examine their abundance before and after surgical resection.The analyses identified a predominance of Firmicutes, Proteobacteria and Bacteroidetes, with less frequent presence of Actinobacteria and Fusobacteria before surgery. At lower taxonomic levels, the most abundant genera were Streptococcus, Prevotella, Haemophilus, Lactobacillus and Veillonella, with lower numbers of Citrobacter and Neisseraceae genus Kingella. HNSCC patients had a significant loss in richness and diversity of microbiota species (p<0.05) compared to the controls. Overall, the Operational Taxonomic Units network shows that the relative abundance of OTU's within genus Streptococcus, Dialister, and Veillonella can be used to discriminate tumor from control samples (p<0.05). Tumor samples lost Neisseria, Aggregatibacter (Proteobacteria), Haemophillus (Firmicutes) and Leptotrichia (Fusobacteria). Paired taxa within family Enterobacteriaceae, together with genus Oribacterium, distinguish OCSCC samples from OPSCC and normal samples (p<0.05). Similarly, only HPV positive samples have an abundance of genus Gemellaceae and Leuconostoc (p<0.05). Longitudinal analyses of samples taken before and after Research PaperOncotarget 51321 www.impactjournals.com/oncotarget surgery, revealed a reduction in the alpha diversity measure after surgery, together with an increase of this measure in patients that recurred (p<0.05). These results suggest that microbiota may be used as HNSCC diagnostic and prognostic biomonitors.

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Substrate Cleavage Profiling Suggests a Distinct Function of Bacteroides fragilis Metalloproteinases (Fragilysin and Metalloproteinase II) at the Microbiome-Inflammation-Cancer Interface

Cited by 28 publications

References 76 publications

Structural and functional diversity of metalloproteinases encoded by the Bacteroides fragilis pathogenicity island

Structural and functional diversity of metalloproteinases encoded by the Bacteroides fragilis pathogenicity island

16S rRNA amplicon sequencing identifies microbiota associated with oral cancer, human papilloma virus infection and surgical treatment

16S rRNA amplicon sequencing identifies microbiota associated with oral cancer, Human Papilloma Virus infection and surgical treatment

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