Activation of pro-matrix metalloproteinase-9 and degradation of gelatin by the surface protease PgtE of Salmonella enterica serovar Typhimurium.
Mammalian matrix metalloproteinases (MMPs) degrade collagen networks in extracellular matrices by cleaving collagen and its denatured form gelatin, and thus enhance migration of mammalian cells. The gastrointestinal pathogen Salmonella enterica survives and grows within host macrophages and dendritic cells, and can disseminate in the host by travelling within infected host cells. Here, we report that S. enterica serovar Typhimurium activates proMMP-9 (gelatinase B) secreted by human primary macrophages, and degrades gelatin after growth within J774A.1 murine macrophage-like cells. Both proMMP-9 activation and gelatin degradation were due to expression of the Salmonella surface protease PgtE. Following intraperitoneal infection in BALB/c mice, the amount of a pgtE deletion derivative was nearly ten-fold lower in the livers and spleens of mice than the amount of wild-type S. enterica, suggesting that PgtE contributes to dissemination of Salmonella in the host. PgtE belongs to the omptin family of bacterial beta-barrel transmembrane proteases. The ortholog of PgtE in Yersinia pestis, Pla, which is central for bacterial virulence in plague, was poor in proMMP-9 activation and in gelatin degradation. To model the evolution of these activities in the omptin barrel, we performed a substitution analysis in Pla and genetically modified it into a PgtE-like gelatinase. Our results indicate that PgtE and Pla have diverged in substrate specificity, and suggest that Salmonella PgtE has evolved to functionally mimic mammalian MMPs.
Ramu
Päivi
P
General Microbiology, Department of Biological and Environmental Sciences, Faculty of Biosciences, University of Helsinki, PO Box 56, FIN-00014 Helsinki, Finland.
Lobo
Leandro Araujo
LA
Kukkonen
Maini
M
Bjur
Eva
E
Suomalainen
Marjo
M
Raukola
Hanna
H
Miettinen
Minja
M
Julkunen
Ilkka
I
Holst
Otto
O
Rhen
Mikael
M
Korhonen
Timo K
TK
Lähteenmäki
Kaarina
K
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D019020:Directed Molecular Evolution; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D005260:Female; D005780:Gelatin / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium / Q000201:enzymology* / Q000472:pathogenicity; D013379:Substrate Specificity; D014774:Virulence / Q000502:physiology
D001426:Bacterial Proteins; D004792:Enzyme Precursors; D005780:Gelatin; D010450:Endopeptidases; C411337:PgtE protein, Salmonella enterica; C078140:Pla protease, Yersinia pestis; D010960:Plasminogen Activators; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9