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The intrinsic immunoglobulin g endopeptidase activity of streptococcal Mac-2 proteins implies a unique role for the enzymatically impaired Mac-2 protein of M28 serotype strains
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Pawel)
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). (Pawel)
2008 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 5, 2183-2188 p.Article in journal (Refereed) Published
Abstract [en]

IdeS, a secreted cysteine protease of the important human pathogen Streptococcus pyogenes, interferes with phagocytic killing by specifically cleaving the heavy chain of immunoglobulin G (IgG). Two allelic variants of the enzyme have been described, the IgG-specific endopeptidase, IdeS (or Mac-1) and Mac-2, a protein with only weak IgG endopeptidase activity, which has been suggested to interfere with opsonophagocytosis by blocking Fcgamma receptors of phagocytic cells. However, despite the fact that Mac-2 proteins interact with Fcgamma receptors, no inhibition of reactive oxygen species (ROS) production, opsonophagocytosis, or streptococcal killing by Mac-2 has been reported. In the present study, Mac-2 proteins are shown to contain IgG endopeptidase activity indistinguishable from the enzymatic activity exhibited by IdeS/Mac-1 proteins. The earlier reported weak IgG endopeptidase activity appears to be unique to Mac-2 of M28 serotype strains (Mac-2(M28)) and is most likely due to the formation of a disulfide bond between the catalytic site cysteine and a cysteine residue in position 257 of Mac-2(M28). Furthermore, Mac-2 proteins are shown to inhibit ROS production ex vivo, independently of the IgG endopeptidase activity of the proteins. Inhibition of ROS generation per se, however, was not sufficient to mediate streptococcal survival in bactericidal assays. Thus, in contrast to earlier studies, implicating separate functions for IdeS and Mac-2 protein variants, the current study suggests that Mac-2 and IdeS are bifunctional proteins, combining Fcgamma receptor binding and IgG endopeptidase activity. This finding implies a unique role for Mac-2 proteins of the M28 serotype, since this serotype has evolved and retained a Mac-2 protein lacking IgG endopeptidase activity.

Place, publisher, year, edition, pages
2008. Vol. 76, no 5, 2183-2188 p.
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-20795DOI: 10.1128/IAI.01422-07PubMedID: 18332209OAI: oai:DiVA.org:umu-20795DiVA: diva2:209564
Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2017-12-13Bibliographically approved
In thesis
1. The streptococcal IgG degrading enzyme IdeS: studies on host-pathogen interactions
Open this publication in new window or tab >>The streptococcal IgG degrading enzyme IdeS: studies on host-pathogen interactions
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The important human pathogen Streptococcus pyogenes causes both mild infections such as pharyngitis and impetigo but also severe life threatening invasive infections.  Specific antibodies (IgG) recognize pathogens and are important mediators for pathogen clearance by the immune defence. S.ipyogenes expresses a highly effective and specific IgG endopeptidase called IdeS (immunoglobulin degrading enzyme of S.ipyogenes). IdeS rescues bacteria from opsonising IgG by cleavage of IgG generating two fragments F(ab´)2 and ½Fc. Moreover, IdeS block ROS production by neutrophils. In this thesis I have studied (i) allelic variants of IdeS and their biological potential, (ii) consequences of ½Fc production for host-pathogen interactions and (iii) IdeS processing by streptococcal and neutrophil proteases.

When investigating the allelic variants of IdeS we could show that in respect to IgG degradation and inhibition of ROS production the allelic variants where indistinguishable, however the allelic variant of serotype M28 appears to be an unique exception as this protein was deficient in IgG cleavage but still inhibited ROS production. Further, the ½Fc fragments produced when IgG is cleaved by IdeS were shown to prime human neutrophils and under ex vivo experimental conditions this increased the bactericidal activity of the neutrophils. Finally, we made the interesting finding that IdeS is N-terminally processed by neutrophil proteases and by the streptococcal protease SpeB, but retain enzymatic activity and was less immunogenic compared to the full length protein.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 43 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1491
Keyword
streptococcus pyogenes, IdeS
National Category
Microbiology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-53706 (URN)978-91-7459-404-1 (ISBN)
Public defence
2012-05-03, Bergasalen, NUS By 27, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2012-04-12 Created: 2012-04-04 Last updated: 2012-05-16Bibliographically approved

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Söderberg, Jenny JohanssonEngström, Patrikvon Pawel-Rammingen, Ulrich
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