TY - JOUR
T1 - Staphylococcus aureus secretes a unique class of neutrophil serine protease inhibitors
AU - Stapels, Daphne A C
AU - Ramyar, Kasra X
AU - Bischoff, Markus
AU - von Köckritz-Blickwede, Maren
AU - Milder, Fin J
AU - Ruyken, Maartje
AU - Eisenbeis, Janina
AU - McWhorter, William J
AU - Herrmann, Mathias
AU - van Kessel, Kok P M
AU - Geisbrecht, Brian V
AU - Rooijakkers, Suzan H M
PY - 2014/8/26
Y1 - 2014/8/26
N2 - Neutrophils are indispensable for clearing infections with the prominent human pathogen Staphylococcus aureus. Here, we report that S. aureus secretes a family of proteins that potently inhibits the activity of neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. The NSPs, but not related serine proteases, are specifically blocked by the extracellular adherence protein (Eap) and the functionally orphan Eap homologs EapH1 and EapH2, with inhibitory-constant values in the low-nanomolar range. Eap proteins are together essential for NSP inhibition by S. aureus in vitro and promote staphylococcal infection in vivo. The crystal structure of the EapH1/NE complex showed that Eap molecules constitute a unique class of noncovalent protease inhibitors that occlude the catalytic cleft of NSPs. These findings increase our insights into the complex pathogenesis of S. aureus infections and create opportunities to design novel treatment strategies for inflammatory conditions related to excessive NSP activity.
AB - Neutrophils are indispensable for clearing infections with the prominent human pathogen Staphylococcus aureus. Here, we report that S. aureus secretes a family of proteins that potently inhibits the activity of neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. The NSPs, but not related serine proteases, are specifically blocked by the extracellular adherence protein (Eap) and the functionally orphan Eap homologs EapH1 and EapH2, with inhibitory-constant values in the low-nanomolar range. Eap proteins are together essential for NSP inhibition by S. aureus in vitro and promote staphylococcal infection in vivo. The crystal structure of the EapH1/NE complex showed that Eap molecules constitute a unique class of noncovalent protease inhibitors that occlude the catalytic cleft of NSPs. These findings increase our insights into the complex pathogenesis of S. aureus infections and create opportunities to design novel treatment strategies for inflammatory conditions related to excessive NSP activity.
KW - animals
KW - bacterial adhesion
KW - bacterial proteins/metabolism
KW - biocatalysis
KW - extracellular space/metabolism
KW - female
KW - humans
KW - leukocyte elastase/antagonists & inhibitors
KW - mice, inbred C57BL
KW - models, molecular
KW - neutrophils/metabolism
KW - serine proteinase inhibitors/metabolism
KW - staphylococcal infections/pathology
KW - staphylococcus aureus/metabolism
KW - dieren
KW - bacteriële adhesie
KW - bacteriële eiwitten/metabolisme
KW - biokatalyse
KW - extracellulaire ruimte/metabolisme
KW - vrouwelijk
KW - mensen
KW - leukocytelastase/antagonisten en remmers
KW - muizen, inteelt C57BL
KW - modellen, moleculair
KW - neutrofielen/metabolisme
KW - serineproteïnaseremmers/metabolisme
KW - stafylokokkeninfecties/pathologie
KW - staphylococcus aureus/metabolisme
U2 - 10.1073/pnas.1407616111
DO - 10.1073/pnas.1407616111
M3 - Article
C2 - 25161283
SN - 0027-8424
VL - 111
SP - 13187
EP - 13192
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
ER -