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The streptococcal cysteine protease SpeB is not a natural immunoglobulin-cleaving enzyme
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
2013 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 6, 2236-2241 p.Article in journal (Refereed) Published
Abstract [en]

The human bacterial pathogen Streptococcus pyogenes has developed a broad variety of virulence mechanisms to evade the actions of the host immune defense. One of the best-characterized factors is the streptococcal cysteine protease SpeB, an important multifunctional protease that contributes to group A streptococcal pathogenesis in vivo. Among many suggested activities, SpeB has been described to degrade various human plasma proteins, including immunoglobulins (Igs). In this study, we show that SpeB has no Ig-cleaving activity under physiological conditions and that only Igs in a reduced state, i.e., semimonomeric molecules, are cleaved and degraded by SpeB. Since reducing conditions outside eukaryotic cells have to be considered nonphysiological and IgG in a reduced state lacks biological effector functions, we conclude that SpeB does not contribute to S. pyogenes virulence through the proteolytic degradation of Igs.

Place, publisher, year, edition, pages
2013. Vol. 81, no 6, 2236-2241 p.
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-74504DOI: 10.1128/IAI.00168-13ISI: 000318855100040OAI: oai:DiVA.org:umu-74504DiVA: diva2:635060
Available from: 2013-07-02 Created: 2013-07-01 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
Open this publication in new window or tab >>Studies on secreted cysteine proteases of Streptococcus pyogenes: IdeS and SpeB
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pathogen Streptococcus pyogenes is a significant cause of human morbidity and mortality. Most of the work in this thesis is focused on streptococcal virulence factor IdeS, but the thesis also features work on SpeB, another streptococcal virulence factor. Both IdeS and SpeB are secreted cysteine proteases and both have previously been shown to degrade human IgG. IgG is the only known substrate for IdeS while SpeB is a more promiscuous protease with a larger number of identified substrates. A significant part of the data presented in this thesis is the result of designing and optimizing methods to detect and accurately measure the proteolytic degradation of IgG. Methods aimed at measuring the binding interactions between enzyme and substrate have also been frequently utilized. I show that IdeS is a monomeric protease, as opposed to previously published data that suggested it to be dimeric. IdeS cleaves the two heavy chains of IgG in a two-step reaction and I demonstrate that the first cleavage is magnitudes faster than the second one. This means that IdeS is a more efficient enzyme than previously thought. The difference in rate cannot completely be explained by a loss of affinity between IdeS and IgG after the cleavage of the first heavy chain. The velocity of IdeS is further increased by the presence of human Cystatin C, via an unknown mechanism. Cystatin C is normally a protease inhibitor and it having an opposite effect is puzzling.The synthesis and evaluation of novel inhibitors are also described. Peptide analogues mimicking the sequence surrounding the scissile bond on IgG - with an amino acid replaced with a more rigid motif - act as specific, but low-affinity, inhibitors of IdeS. The peptide analogues’ inhibitory capacity for SpeB and papain was also assayed.When it comes to SpeB, I show that it does not have IgG as a substrate under physiological conditions, in contrast to what was previously thought. This thesis does not only present findings on the IgG degrading capacity of IdeS and SpeB but also include data on fundamental enzymatic properties for these proteases.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. 49 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1646
Keyword
Streptococcus pyogenes, Group A Streptococci, GAS, virulence factor, IdeS, SpeB, cysteine protease, protease inhibitor, IgG, immune evasion
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biotechnology
Identifiers
urn:nbn:se:umu:diva-88223 (URN)978-91-7601-048-8 (ISBN)
Public defence
2014-05-27, Sal E04, by 6E, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2014-05-06 Created: 2014-04-28 Last updated: 2014-05-06Bibliographically approved

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Persson, HelenaVindebro, Reinevon Pawel-Rammingen, Ulrich

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