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Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions

Author

Listed:
  • Valentina Palmerini

    (IEO, European Institute of Oncology IRCCS)

  • Silvia Monzani

    (IEO, European Institute of Oncology IRCCS)

  • Quentin Laurichesse

    (University of Copenhagen
    Faculty of Health and Medical University of Copenhagen)

  • Rihab Loudhaief

    (University of Copenhagen
    Faculty of Health and Medical University of Copenhagen)

  • Sara Mari

    (IEO, European Institute of Oncology IRCCS)

  • Valentina Cecatiello

    (IEO, European Institute of Oncology IRCCS)

  • Vincent Olieric

    (Paul Scherrer Institute)

  • Sebastiano Pasqualato

    (IEO, European Institute of Oncology IRCCS)

  • Julien Colombani

    (University of Copenhagen
    Faculty of Health and Medical University of Copenhagen)

  • Ditte S. Andersen

    (University of Copenhagen
    Faculty of Health and Medical University of Copenhagen)

  • Marina Mapelli

    (IEO, European Institute of Oncology IRCCS)

Abstract

The Drosophila tumour necrosis factor (TNF) ligand-receptor system consists of a unique ligand, Eiger (Egr), and two receptors, Grindelwald (Grnd) and Wengen (Wgn), and therefore provides a simple system for exploring the interplay between ligand and receptors, and the requirement for Grnd and Wgn in TNF/Egr-mediated processes. Here, we report the crystallographic structure of the extracellular domain (ECD) of Grnd in complex with Egr, a high-affinity hetero-hexameric assembly reminiscent of human TNF:TNFR complexes. We show that ectopic expression of Egr results in internalisation of Egr:Grnd complexes in vesicles, a step preceding and strictly required for Egr-induced apoptosis. We further demonstrate that Wgn binds Egr with much reduced affinity and is localised in intracellular vesicles that are distinct from those containing Egr:Grnd complexes. Altogether, our data provide insight into ligand-mediated activation of Grnd and suggest that distinct affinities of TNF ligands for their receptors promote different and non-redundant cellular functions.

Suggested Citation

  • Valentina Palmerini & Silvia Monzani & Quentin Laurichesse & Rihab Loudhaief & Sara Mari & Valentina Cecatiello & Vincent Olieric & Sebastiano Pasqualato & Julien Colombani & Ditte S. Andersen & Marin, 2021. "Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22080-9
    DOI: 10.1038/s41467-021-22080-9
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