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TitleA helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis.
Journal, issue, pagesSci Immunol, Vol. 9, Issue 102, Page eadl1467, Year 2024
Publish dateDec 6, 2024
AuthorsSina Bohnacker / Fiona D R Henkel / Franziska Hartung / Arie Geerlof / Sandra Riemer / Ulrich F Prodjinotho / Eya Ben Salah / André Santos Dias Mourão / Stefan Bohn / Tarvi Teder / Dominique Thomas / Robert Gurke / Christiane Boeckel / Minhaz Ud-Dean / Ann-Christine König / Alessandro Quaranta / Francesca Alessandrini / Antonie Lechner / Benedikt Spitzlberger / Agnieszka M Kabat / Edward Pearce / Jesper Z Haeggström / Stefanie M Hauck / Craig E Wheelock / Per-Johan Jakobsson / Michael Sattler / David Voehringer / Matthias J Feige / Clarissa Prazeres da Costa / Julia Esser-von Bieren /
PubMed AbstractThe molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using (), we show that helminthic glutamate ...The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using (), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E (PGE) as a major immune regulatory mechanism of heGDH. The induction of PGE and other immunoregulatory factors, including IL-12 family cytokines and indoleamine 2,3-dioxygenase 1, by heGDH required p300-mediated histone acetylation, whereas the enzyme's catalytic activity suppressed the synthesis of type 2-promoting leukotrienes by macrophages via 2-hydroxyglutarate. By contrast, the induction of immunoregulatory factors involved the heGDH N terminus by potentially mediating interactions with cellular targets (CD64 and GPNMB) identified by proteomics. Type 2 cytokines counteracted suppressive effects of heGDH on host defense, indicating that type 2 immunity can limit helminth-driven immune evasion. Thus, helminths harness a ubiquitous metabolic enzyme to epigenetically target type 2 macrophage activation and establish chronicity.
External linksSci Immunol / PubMed:39642243
MethodsEM (single particle)
Resolution2.56 - 2.69 Å
Structure data

EMDB-18456: CryoEM map of hexamer worm glutamate dehydrogenase
Method: EM (single particle) / Resolution: 2.62 Å

EMDB-19692: Hexameric worm glutamate dehydrogenase (N-term. deletion 1-33)
Method: EM (single particle) / Resolution: 2.56 Å

EMDB-19693: Hexameric worm glutamate dehydrogenase (C136S)
Method: EM (single particle) / Resolution: 2.69 Å

Source
  • Heligmosomoides bakeri (invertebrata)

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