@article{978681c671414bfb9c3134e2af25686e,
title = "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 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.",
author = "Alice Soragni and Shida Yousefi and Christina Stoeckle and Soriaga, {Angela B.} and Sawaya, {Michael R.} and Evelyne Kozlowski and In{\`e}s Schmid and Susanne Radonjic-Hoesli and Sebastien Boutet and Williams, {Garth J.} and Marc Messerschmidt and Seibert, {M. Marvin} and Duilio Cascio and Nadia Zatsepin and Manfred Burghammer and Christian Riekel and Colletier, {Jacques Philippe} and Roland Riek and Eisenberg, {David S.} and Simon, {Hans Uwe}",
note = "Funding Information: We thank all patients and collaborating clinicians for providing blood and tissue samples for the research reported here. We thank M. Capel, K. Rajashankar, N. Sukumar, J. Schuermann, I. Kourinov, and F. Murphy at NECAT beamlines 24-ID at APS, which are supported by grants from the National Center for Research Resources ( 5P41RR015301-10 ) and the National Institute of General Medical Sciences ( 8 P41 GM103403-10 ) from the NIH . Use of the APS is supported by the DOE under Contract DE-AC02-06CH11357 . We thank Matthias Frank, Mark S. Hunter, Michael J. Bogan, and John Miao for helpful experimental suggestions and scientific discussion; Anton Barty for help with XFEL image conversion and preliminary data analysis; and Stephan Stern and Tom Pardini for helping with the XFEL motor script. We thank the ESRF and LCLS staff for technical support. We acknowledge the EMEZ facility at ETH for support with the electron microscopy experiments, in particular Elisabeth Gruber-Miller, Fabian Gramm, and Peter Tittmann. We also acknowledge the use of instruments at the Electron Imaging Center for NanoMachines supported by NIH ( 1S10RR23057 ) and CNSI at UCLA . This work was supported by grants from the Swiss National Science Foundation (to R.R. and H.-U.S.); the National Science Foundation ( MCB 1021557 to N.A.Z. and MCB 0958111 to D.S.E.); the Allergie-Stiftung Ulrich M{\"u}ller-Gierok (to S.R.-H. and H.-U.S.); the German Research Foundation (to C.S.); and from the NIH ( AG029430 ), the Keck Foundation , and HHMI (to D.S.E.). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = mar,
day = "19",
doi = "10.1016/j.molcel.2015.01.026",
language = "English (US)",
volume = "57",
pages = "1011--1021",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}