Activation of pro-matrix metalloproteinase-9 and degradation of gelatin by the surface protease PgtE of Salmonella enterica serovar Typhimurium

Ramu, Päivi; Lobo, Leandro Araújo; Kukkonen, Maini; Bjur, Eva; Suomalainen, Maarit; Raukola, Hanna; Miettinen, Minja; Julkunen, Ilkka; Holst, Otto; Rhen, Mikael; Korhonen, Timo; Lähteenmäki, Kaarina

doi:10.1016/j.ijmm.2007.06.004

Cited by 30 publications

(55 citation statements)

References 61 publications

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“…Additionally, they are thought to affect the activity of inflammatory molecules (59). S. typhimurium and other bacterial species have been reported to secrete proteases that activate inactive proenzyme forms of matrix metalloproteinases, which may promote bacterial spreading through the host tissues (60). Here we have shown that mmp9 expression is a target of the TLR5 pathway that is induced by Salmonella flagellin.…”

Section: Discussionmentioning

confidence: 66%

Transcriptome Profiling and Functional Analyses of the Zebrafish Embryonic Innate Immune Response to Salmonella Infection

Stockhammer

Zakrzewska

Hegedűs

et al. 2009

The Journal of Immunology

197

204

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Due to the clear separation of innate immunity from adaptive responses, the externally developing zebrafish embryo represents a useful in vivo model for identification of innate host determinants of the response to bacterial infection. Here we performed a time-course transcriptome profiling study and gene ontology analysis of the embryonic innate immune response to infection with two model Salmonella strains that elicit either a lethal infection or an attenuated response. The transcriptional response to infection with both the lethal strain and the avirulent LPS O-Ag mutant strain showed clear conservation with host responses detected in other vertebrate models and human cells, including induction of genes encoding cell surface receptors, signaling intermediates, transcription factors, and inflammatory mediators. Furthermore, our study led to the identification of a large set of novel immune response genes and infection markers, the future functional characterization of which will support vertebrate genome annotation. From the time series and bacterial strain comparisons, matrix metalloproteinase genes, including mmp9, were among the most consistent infection-responsive genes. Purified Salmonella flagellin also strongly induced mmp9 expression. Using knockdown analysis, we showed that this gene was downstream of the zebrafish homologs of the flagellin receptor TLR5 and the adaptor MyD88. Additionally, flagellin-mediated induction of other inflammation markers, including il1b, il8, and cxcl-C1c, was reduced upon Tlr5 knockdown as well as expression of irak3, a putative negative TLR pathway regulator. Finally, we showed that induction of il1b, mmp9, and irak3 requires Myd88-dependent signaling, while ifn1 and il8 were induced Myd88 independently during Salmonella infection.

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Section: Discussionmentioning

confidence: 66%

Transcriptome Profiling and Functional Analyses of the Zebrafish Embryonic Innate Immune Response to Salmonella Infection

Stockhammer

Zakrzewska

Hegedűs

et al. 2009

The Journal of Immunology

197

204

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“…We hypothesize that amino acid residues at the sites where majority of the differences are found promote, or the corresponding residues in OmpT/SopA/Yco prevent, the interaction with PAI-1. This hypothesis is supported by mutagenesis scanning, loop swapping, and substitution analyses showing that the polypeptide substrate selectivities of Pla, OmpT, and PgtE for plasminogen and gelatin are dictated by their surface loops (22,32,48).…”

Section: Discussionmentioning

confidence: 87%

“…S. enterica serovar Typhimurium rarely causes systemic infections, but other serovars, including severe pathogens S. Typhi and S. Paratyphi, which typically cause systemic infections, possess pgtE genes whose predicted protein sequences are at least 98% identical to that of PgtE of S. Typhimurium (49). PgtE is a poor plasminogen activator (22) but promotes growth of S. Typhimurium inside mouse macrophages and its systemic spread in mice (35,48). Plasminogen activation has not been reported in salmonellosis in vivo, but recent findings have suggested that S. enterica serovar Typhimurium also engages the plasminogen system to advance cell migration (35,48).…”

Section: Discussionmentioning

confidence: 99%

“…PgtE is a poor plasminogen activator (22) but promotes growth of S. Typhimurium inside mouse macrophages and its systemic spread in mice (35,48). Plasminogen activation has not been reported in salmonellosis in vivo, but recent findings have suggested that S. enterica serovar Typhimurium also engages the plasminogen system to advance cell migration (35,48). Endotoxin-activated macrophages show increased surface-located plasminogen activation (67), and through inactivation of PAI-1 and the subsequent increase in plasminogen activation, PgtE may increase proteolysis and mobility of phagocytes as well as of bacterial cells that are released from inflammatory phagocytes (38).…”

Section: Discussionmentioning

confidence: 99%

“…The chromosomal ompT and the plasmid-encoded ompT P genes of E. coli IHE 3034, sopA of Shigella flexneri M90T, kop (Klebsiella outer membrane protease) of Klebsiella pneumoniae 342, epo (plaA) of Erwinia pyrifoliae Ep1/96, and the Yersinia chromosomal omptin genes ycoA of Y. pestis KIM D34 and ycoB of Y. pseudotuberculosis IP 32953 were cloned and expressed as described earlier (32,33). S. enterica and E. coli XL1 were cultivated as described previously (22,48). Y. pestis was cultivated over two nights at 37°C on brain heart infusion (BHI) plates, inoculated in BHI broth with hemin (40 g/ml), and cultivated twice over two nights at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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The Omptins ofYersinia pestisandSalmonella entericaCleave the Reactive Center Loop of Plasminogen Activator Inhibitor 1

et al. 2010

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Plasminogen activator inhibitor 1 (PAI-1) is a serine protease inhibitor (serpin) and a key molecule that regulates fibrinolysis by inactivating human plasminogen activators. Here we show that two important human pathogens, the plague bacterium Yersinia pestis and the enteropathogen Salmonella enterica serovar Typhimurium, inactivate PAI-1 by cleaving the R346-M347 bait peptide bond in the reactive center loop. No cleavage of PAI-1 was detected with Yersinia pseudotuberculosis, an oral/fecal pathogen from which Y. pestis has evolved, or with Escherichia coli. The cleavage and inactivation of PAI-1 were mediated by the outer membrane proteases plasminogen activator Pla of Y. pestis and PgtE protease of S. enterica, which belong to the omptin family of transmembrane endopeptidases identified in Gram-negative bacteria. Cleavage of PAI-1 was also detected with the omptins Epo of Erwinia pyrifoliae and Kop of Klebsiella pneumoniae, which both belong to the same omptin subfamily as Pla and PgtE, whereas no cleavage of PAI-1 was detected with omptins of Shigella flexneri or E. coli or the Yersinia chromosomal omptins, which belong to other omptin subfamilies. The results reveal a novel serpinolytic mechanism by which enterobacterial species expressing omptins of the Pla subfamily bypass normal control of host proteolysis.Plasminogen activator inhibitor 1 (PAI-1) is a key regulator of the mammalian fibrinolytic/plasminogen system (29, 37). The fibrinolytic system comprises the serine protease zymogen plasminogen, urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), PAI-1, and plasmin inhibitor ␣ 2 -antiplasmin (␣ 2 AP) (for a review, see reference 52). Plasminogen is converted to plasmin, which is a broad-spectrum serine protease that dissolves fibrin in blood clots, degrades laminin of basement membranes, and activates matrix metalloproteinases that degrade collagens and gelatins in tissue barriers. Herewith, plasmin controls physiological processes such as fibrinolysis/coagulation, cell migration and invasion, and tumor metastasis (29, 37). PAI-1 maintains normal hemostasis by inhibiting the function of the plasminogen activators tPA and uPA, which are serine proteases and highly specific for cleavage of the plasminogen molecule. tPA binds to fibrin and is associated with plasmin-mediated breakdown of fibrin clots, whereas uPA has low affinity for fibrin and associates with cell surface proteolysis, cellular migration, and damage of tissue barriers (52).The mammalian fibrinolytic and coagulation systems are targeted by invasive bacterial pathogens during infection (reviewed in references 6, 11, 34, and 61). In bacterial sepsis, increased production of fibrin clots at a damaged endothelium results from enhanced thrombin-catalyzed fibrin generation and from an increased serum level of PAI-1. Coagulation can protect the host by activating immune systems or by physically restraining the bacteria (6,15,25,41). On the other hand, several invasive bacterial pathogens enhance fibrinolysis eithe...

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Bacterial Abuse of Mammalian Extracellular Proteases during Tissue Invasion and Infection

Weber

Herwald

Hammerschmidt

2012

Matrix Proteases in Health and Disease

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Activation of pro-matrix metalloproteinase-9 and degradation of gelatin by the surface protease PgtE of Salmonella enterica serovar Typhimurium

Cited by 30 publications

References 61 publications

Transcriptome Profiling and Functional Analyses of the Zebrafish Embryonic Innate Immune Response to Salmonella Infection

Transcriptome Profiling and Functional Analyses of the Zebrafish Embryonic Innate Immune Response to Salmonella Infection

The Omptins ofYersinia pestisandSalmonella entericaCleave the Reactive Center Loop of Plasminogen Activator Inhibitor 1

Bacterial Abuse of Mammalian Extracellular Proteases during Tissue Invasion and Infection

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