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

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 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.

SUBMITTER: Soragni A

PROVIDER: S-EPMC4904734 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Soragni Alice A Yousefi Shida S Stoeckle Christina C Soriaga Angela B AB Sawaya Michael R MR Kozlowski Evelyne E Schmid Inès I Radonjic-Hoesli Susanne S Boutet Sebastien S Williams Garth J GJ Messerschmidt Marc M Seibert M Marvin MM Cascio Duilio D Zatsepin Nadia A NA Burghammer Manfred M Riekel Christian C Colletier Jacques-Philippe JP Riek Roland R Eisenberg David S DS Simon Hans-Uwe HU

Molecular cell 20150226 6

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 wi ...[more]

PMID: 25728769

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Dataset Information

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

Publications

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

Similar Datasets

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