In this section
@article{Giblin:2025:10.1016/j.jbc.2025.108448,
author = {Giblin, SP and McKenna, S and Matthews, S and Sriskandan, S and Pease, JE},
doi = {10.1016/j.jbc.2025.108448},
journal = {Journal of Biological Chemistry},
title = {The N-terminal ELR+ motif of the neutrophil attractant CXCL8 confers susceptibility to degradation by the Group A Streptococcal protease, SpyCEP},
url = {http://dx.doi.org/10.1016/j.jbc.2025.108448},
volume = {301},
year = {2025}
}
TY - JOUR
AB - Streptococcus pyogenes (Group A Streptococcus or GAS) is a major human pathogen for which an effective vaccine is highly desirable. Invasive S. pyogenes strains evade the host immune response in part by producing a cell envelope protease, SpyCEP. This neutralizes chemokines containing an N-terminal Glu-Leu-Arg motif (ELR+ chemokines) by cleavage at a distal C-terminal site within the chemokine. SpyCEP is a component of several S. pyogenes vaccines, yet the molecular determinants underlying substrate selectivity are poorly understood. We hypothesized that chemokine recognition and cleavage is a multistep process involving distinct domains of both substrate and enzyme. We generated a panel of recombinant CXCL8 variants where domains of the chemokine were exchanged or mutated. Chemokine degradation by SpyCEP was assessed by SDS-PAGE, Western blot, and ELISA. Extension of the CXCL8 N-terminus was found to inhibit chemokine cleavage. Reciprocal exchanges of the N-termini of CXCL8 with that of the ELR- chemokine CXCL4 resulted in the generation of loss of function and gain of function substrates. This suggested a key role for the ELR motif in substrate recognition, which was supported directly by alanine substitution of the ELR motif of CXCL8, impairing the parameters, KM, Vmax, and Kcat in kinetic assays with SpyCEP. Collectively, our findings identify the N-terminal ELR motif as a major determinant for recognition by SpyCEP and expose a vulnerability in the mechanism by which the protease recognises its substrates. This likely presents potential avenues for therapeutic intervention via targeted vaccine design and small molecule inhibition.
AU - Giblin,SP
AU - McKenna,S
AU - Matthews,S
AU - Sriskandan,S
AU - Pease,JE
DO - 10.1016/j.jbc.2025.108448
PY - 2025///
SN - 0021-9258
TI - The N-terminal ELR+ motif of the neutrophil attractant CXCL8 confers susceptibility to degradation by the Group A Streptococcal protease, SpyCEP
T2 - Journal of Biological Chemistry
UR - http://dx.doi.org/10.1016/j.jbc.2025.108448
VL - 301
ER -
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