The human protease inhibitor cystatin C is an activating cofactor for the streptococcal cysteine protease IdeS.
Human cystatin C is considered the physiologically most important inhibitor of endogenous papain-like cysteine proteases. We present here an unexpected function of cystatin C. Instead of acting as an inhibitor, cystatin C acts as a facultative, endogenous cofactor for the papain-like IgG-cleaving enzyme IdeS of the human pathogen Streptococcus pyogenes. IdeS activity is not dependent on cystatin C, but is significantly enhanced in the presence of cystatin C. We report a protease inhibitor that accelerates the activity of its putative target protease and a unique example of how a host protease inhibitor is "hijacked" by a bacterial protease to increase its activity. This finding has important implications for the view on protease-inhibitor interactions, and is relevant to consider in the therapeutic use of protease inhibitors.
Vincents
Bjarne
B
Department of Laboratory Medicine, Division of Clinical Chemistry and Pharmacology, Lund University, University Hospital, Lund, Sweden.
Vindebro
Reine
R
Abrahamson
Magnus
M
von Pawel-Rammingen
Ulrich
U
D001426:Bacterial Proteins / Q000378:metabolism*; D055316:Cystatin C; D015891:Cystatins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D006801:Humans; D006868:Hydrolysis; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D011480:Protease Inhibitors / Q000378:metabolism*; D011485:Protein Binding; D013291:Streptococcus / Q000201:enzymology*; D020349:Surface Plasmon Resonance
D001426:Bacterial Proteins; C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D007074:Immunoglobulin G; C442815:Mac-1-like protein, Streptococcus; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases