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Infection and Immunity, May 2008, p. 2183-2188, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01422-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Jenny Johansson Söderberg, Patrik Engström, and Ulrich von Pawel-Rammingen*

Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden

Received 23 October 2007/ Returned for modification 29 November 2007/ Accepted 27 February 2008

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 Fc{gamma} receptors of phagocytic cells. However, despite the fact that Mac-2 proteins interact with Fc{gamma} 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-2M28) 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-2M28. 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 Fc{gamma} 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.

* Corresponding author. Mailing address: Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden. Phone: 46 90 785 6705. Fax: 46 90 772630. E-mail: ulrich.von-pawel{at}molbiol.umu.se

{triangledown} Published ahead of print on 10 March 2008.

Editor: J. N. Weiser

Infection and Immunity, May 2008, p. 2183-2188, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01422-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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