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  • Identification of a domain critical for Staphylococcus aureus LukED receptor targeting and lysis of erythrocytes

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    Embargoed until: 2021-10-13
    Author(s)
    Vasquez, MT
    Lubkin, A
    Reyes-Robles, T
    Day, CJ
    Lacey, KA
    Jennings, MP
    Torres, VJ
    Griffith University Author(s)
    Jennings, Michael P.
    Day, Christopher J.
    Year published
    2020
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    Abstract
    Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton-Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The ...
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    Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton-Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC and the role this plays in hemolysis are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE-LukS-PV chimeras, in which areas of sequence divergence (divergence regions, or DRs) were swapped between the toxins. We found that two regions of LukE's rim domain contribute to hemolysis, namely residues 57-75 (DR1) and residues 182-196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE-DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.
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    Journal Title
    Journal of Biological Chemistry
    Volume
    295
    Issue
    50
    DOI
    https://doi.org/10.1074/jbc.RA120.015757
    Copyright Statement
    This research was originally published in Journal of Biological Chemistry (JBC). Vasquez, MT; Lubkin, A; Reyes-Robles, T; Day, CJ; Lacey, KA; Jennings, MP; Torres, VJ, Identification of a domain critical for Staphylococcus aureus LukED receptor targeting and lysis of erythrocytes, Journal of Biological Chemistry, 2020, 295 (50), pp. 17241-17250. Copyright the American Society for Biochemistry and Molecular Biology. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive version.
    Subject
    Chemical Sciences
    Biological Sciences
    Medical and Health Sciences
    ACKR1
    DARC
    Duffy
    Staphylococcus aureus (S. aureus)
    bacterial pathogenesis
    Publication URI
    http://hdl.handle.net/10072/400808
    Collection
    • Journal articles

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