Toxicity of eosinophil MBP is repressed by intracellular crystallization and promoted by extracellular aggregation.

Soragni, Alice; Yousefi, Shida; Stoeckle, Christina; Soriaga, Angela B; Sawaya, Michael R; Kozlowski, Eveline; Schmid, Ines; Radonjic-Hoesli, Susanne; Boutet, Sebastien; Williams, Garth J; Messerschmidt, Marc; Seibert, M Marvin; Cascio, Duilio; Zatsepin, Nadia A; Burghammer, Manfred; Riekel, Christian; Colletier, Jacques-Philippe; Riek, Roland; Eisenberg, David S and Simon, Hans-Uwe (2015). Toxicity of eosinophil MBP is repressed by intracellular crystallization and promoted by extracellular aggregation. Molecular cell, 57(6), pp. 1011-1021. Cell Press 10.1016/j.molcel.2015.01.026

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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 the eosinophil 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Yousefi, Shida; Kozlowski, Eveline; Schmid, Ines and Simon, Hans-Uwe

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1097-2765

Publisher:

Cell Press

Language:

English

Submitter:

Debora Scherrer

Date Deposited:

23 Jul 2015 16:20

Last Modified:

26 May 2016 10:13

Publisher DOI:

10.1016/j.molcel.2015.01.026

PubMed ID:

25728769

BORIS DOI:

10.7892/boris.70451

URI:

https://boris.unibe.ch/id/eprint/70451

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