Toxicity of Eosinophil MBP Is Repressed by Intracellular Crystallization and Promoted by Extracellular Aggregation

Alice Soragni, Shida Yousefi, Christina Stoeckle, Angela B. Soriaga, Michael R. Sawaya, Evelyne Kozlowski, Inès Schmid, Susanne Radonjic-Hoesli, Sebastien Boutet, Garth J. Williams, Marc Messerschmidt, M. Marvin Seibert, Duilio Cascio, Nadia Zatsepin, Manfred Burghammer, Christian Riekel, Jacques Philippe Colletier, Roland Riek, David S. Eisenberg, Hans Uwe Simon

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Eosinophils are white blood cells that function in innate immunity and participate in the pathogenesis of various inflammatory and neoplastic disorders. Their secretory granules contain four cytotoxic proteins, including the eosinophil major basic protein (MBP-1). How MBP-1 toxicity is controlled within theeosinophil itself and activated upon extracellular release is unknown. Here we show how intragranular MBP-1 nanocrystals restrain toxicity, enabling its safe storage, and characterize them with an X-ray-free electron laser. Following eosinophil activation, MBP-1 toxicity is triggered by granule acidification, followed by extracellular aggregation, which mediates the damage to pathogens and host cells. Larger non-toxic amyloid plaques are also present in tissues of eosinophilic patients in a feedback mechanism that likely limits tissue damage under pathological conditions of MBP-1 oversecretion. Our results suggest that MBP-1 aggregation is important for innate immunity and immunopathology mediated by eosinophils and clarify how its polymorphic self-association pathways regulate toxicity intra- and extracellularly.

Original languageEnglish (US)
Pages (from-to)1011-1021
Number of pages11
JournalMolecular Cell
Volume57
Issue number6
DOIs
StatePublished - Mar 19 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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