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* Department of Surgery, University of California San Diego, La Jolla, CA 92093;
Graduate Program Cellular and Molecular Medicine, Johns Hopkins University, Baltimore, MD 21205;
Klinikum Rechts der Isar, Technische Universität München, and Helmholtz Center Munich Clinical Cooperation Group Innate Immunity, Munich, Germany;
Uniformed Services University of the Health Sciences, Bethesda, MD 20814; and
¶ Institute for Organic and Biomolecular Chemistry, University of Göttingen, Göttingen, Germany
Heat shock proteins (hsps) are intracellular chaperones that play a key role in the recovery from stress. Hsp70, the major stress-induced hsp, has been found in the extracellular medium and is capable of activating immune cells. The mechanism involved in Hsp70 release is controversial because this protein does not present a consensual secretory signal. In this study, we have shown that Hsp70 integrates into artificial lipid bilayer openings of ion conductance pathways. In addition, this protein was found inserted into the plasma membrane of cells after stress. Hsp70 was released into the extracellular environment in a membrane-associated form, sharing the characteristics of this protein in the plasma membrane. Extracellular membranes containing Hsp70 were at least 260-fold more effective than free recombinant protein in inducing TNF-
production as an indicator of macrophage activation. These observations suggest that Hsp70 translocates into the plasma membrane after stress and is released within membranous structures from intact cells, which could act as a danger signal to activate the immune system.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant GM 50878 (to A.D.M.) and Deutsche Forschungsgemeinschaft Grant MU 1238 7/2 (to G.M.).
2 Address correspondence and reprint requests to Dr. Antonio De Maio, University of California San Diego Department of Surgery, 9500 Gilman Drive, Number 0739, La Jolla, CA 92093. E-mail address: ademaio{at}ucsd.edu
3 Abbreviations used in this paper: hsp, heat shock protein; CTX, cholera toxin; DAPI, 4',6'-diamidino-2-phenlyindole; DRM, detergent-resistant membrane; ECM, extracellular membrane; GA, geldanamycin; GM1, monosialoganglioside; HS, heat shock; Hsc70, heat shock cognate 70; MβCD, methyl-b-cyclodextrin; PFA, paraformaldehyde; POPE, 1-palmitoyl-2-oleoyl-phosphatidylethanolamine; POPS, 1-palmitoyl-2-oleoyl-phosphatidylserine; PS, phosphatidylserine; SF, serum free; sulfo-NHS-biotin, N-hydroxysulfosuccinimidobiotin; WT, wild type; YFP, yellow fluorescent protein.
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