Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies.

Endo-β-N-acetylglucosaminidases (ENGases) that specifically hydrolyze the Asn297-linked glycan on immunoglobulin G (IgG) antibodies, the major molecular determinant of fragment crystallizable (Fc) γ receptor (FcγR) binding, are exceedingly rare. All previously characterized IgG-specific ENGases are multi-domain proteins secreted as an immune evasion strategy by Streptococcus pyogenes strains. Here, using in silico analysis and mass spectrometry techniques, we identified a family of single-domain ENGases secreted by pathogenic corynebacterial species that exhibit strict specificity for IgG antibodies. By X-ray crystallographic and surface plasmon resonance analyses, we found that the most catalytically efficient IgG-specific ENGase family member recognizes both protein and glycan components of IgG. Employing in vivo models, we demonstrated the remarkable efficacy of this IgG-specific ENGase in mitigating numerous pathologies that rely on FcγR-mediated effector functions, including T and B lymphocyte depletion, autoimmune hemolytic anemia, and antibody-dependent enhancement of dengue disease, revealing its potential for treating and/or preventing a wide range of IgG-mediated diseases in humans. Copyright © 2024 Elsevier Inc. All rights reserved.

Citation

Diego E Sastre, Stylianos Bournazos, Jonathan Du, E Josephine Boder, Julia E Edgar, Tala Azzam, Nazneen Sultana, Maros Huliciak, Maria Flowers, Lea Yoza, Ting Xu, Tatiana A Chernova, Jeffrey V Ravetch, Eric J Sundberg. Potent efficacy of an IgG-specific endoglycosidase against IgG-mediated pathologies. Cell. 2024 Nov 27;187(24):6994-7007.e12

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PMID: 39437779

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