TY - JOUR
T1 - Host–receptor post-translational modifications refine staphylococcal leukocidin cytotoxicity
AU - Tromp, Angelino T.
AU - van Gent, Michiel
AU - Jansen, Joris P.
AU - Scheepmaker, Lisette M.
AU - Velthuizen, Anneroos
AU - de Haas, Carla J.C.
AU - van Kessel, Kok P.M.
AU - Bardoel, Bart W.
AU - Boettcher, Michael
AU - McManus, Michael T.
AU - van Strijp, Jos A.G.
AU - Lebbink, Robert Jan
AU - Haas, Pieter Jan A.
AU - Spaan, András N.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Staphylococcal bi-component pore-forming toxins, also known as leukocidins, target and lyse human phagocytes in a receptor-dependent manner. S-components of the leukocidins Panton-Valentine leukocidin (PVL), γ-haemolysin AB (HlgAB) and CB (HlgCB), and leukocidin ED (LukED) specifically employ receptors that belong to the class of G-protein coupled receptors (GPCRs). Although these receptors share a common structural architecture, little is known about the conserved characteristics of the interaction between leukocidins and GPCRs. In this study, we investigated host cellular pathways contributing to susceptibility towards S. aureus leukocidin cytotoxicity. We performed a genome-wide CRISPR/Cas9 library screen for toxin-resistance in U937 cells sensitized to leukocidins by ectopic expression of different GPCRs. Our screen identifies posttranslational modification (PTM) pathways involved in the sulfation and sialylation of the leukocidin-receptors. Subsequent validation experiments show differences in the impact of PTM moieties on leukocidin toxicity, highlighting an additional layer of refinement and divergence in the staphylococcal host-pathogen interface. Leukocidin receptors may serve as targets for anti-staphylococcal interventions and understanding toxin-receptor interactions will facilitate the development of innovative therapeutics. Variations in the genes encoding PTM pathways could provide insight into observed differences in susceptibility of humans to infections with S. aureus.
AB - Staphylococcal bi-component pore-forming toxins, also known as leukocidins, target and lyse human phagocytes in a receptor-dependent manner. S-components of the leukocidins Panton-Valentine leukocidin (PVL), γ-haemolysin AB (HlgAB) and CB (HlgCB), and leukocidin ED (LukED) specifically employ receptors that belong to the class of G-protein coupled receptors (GPCRs). Although these receptors share a common structural architecture, little is known about the conserved characteristics of the interaction between leukocidins and GPCRs. In this study, we investigated host cellular pathways contributing to susceptibility towards S. aureus leukocidin cytotoxicity. We performed a genome-wide CRISPR/Cas9 library screen for toxin-resistance in U937 cells sensitized to leukocidins by ectopic expression of different GPCRs. Our screen identifies posttranslational modification (PTM) pathways involved in the sulfation and sialylation of the leukocidin-receptors. Subsequent validation experiments show differences in the impact of PTM moieties on leukocidin toxicity, highlighting an additional layer of refinement and divergence in the staphylococcal host-pathogen interface. Leukocidin receptors may serve as targets for anti-staphylococcal interventions and understanding toxin-receptor interactions will facilitate the development of innovative therapeutics. Variations in the genes encoding PTM pathways could provide insight into observed differences in susceptibility of humans to infections with S. aureus.
KW - Bi-component pore-forming toxins
KW - G-protein coupled receptors
KW - Leukocidins
KW - Post-translational modifications
KW - Receptors
KW - Staphylococcus aureus
UR - http://www.scopus.com/inward/record.url?scp=85079115563&partnerID=8YFLogxK
U2 - 10.3390/toxins12020106
DO - 10.3390/toxins12020106
M3 - Article
C2 - 32041354
AN - SCOPUS:85079115563
SN - 2072-6651
VL - 12
JO - Toxins
JF - Toxins
IS - 2
M1 - 106
ER -