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ERP57 Membrane Translocation Dictates the Immunogenicity of Tumor Cell Death by Controlling the Membrane Translocation of Calreticulin¹

GenCal, Paris, France

Several pieces of experimental evidence indicate the following: 1) the most efficient antitumor treatments (this principle applies on both chemotherapy and radiotherapy) are those that induce immunogenic cell death and are able to trigger a specific antitumor immune response; and 2) the immunogenicity of cell death depends very closely on the plasma membrane quantity of calreticulin (CRT), an endoplasmic reticulum (ER) stress protein exposed to the cell membrane after immunogenic treatment. Nevertheless, the mechanisms implicated in CRT translocation are unknown. CRT is known to interact in the ER with ERP57, another ER stress protein. I sought to determine whether ERP57 would have any role in tumor immunogenicity. In this article I report that CRT exposure is controlled by ERP57 exposure. CRT and ERP57 are translocated together in the same molecular complex. ERP57 knockdown suppressed CRT exposure as well as phagocytosis by dendritic cells and abolished the immunogenicity in vivo. Knockdown or the absence of CRT abolishes ERP57 exposure. Administration of recombinant ERP57, unlike the administration of recombinant CRT, did not restore the immunogenicity of CRT or ERP57 small interfering RNA-transfected tumor cells. Together, these studies identify ERP57 as a key protein that controls immunogenicity by controlling CRT exposure and illustrate the ability of ERP57 to serve as a new molecular marker of immunogenicity.

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 in part by a grant from GenCal and by a fellowship to M.O. from Association pour la Recherche sur le Cancer (ARC).

M.O. performed the in vivo and in vitro experiments, conducted the data analysis, conceived and designed the study and wrote the manuscript.

² Address correspondence and reprint requests to Dr. Michel Obeid, GenCal, 43 Rue Violet, F-75015 Paris, France. E-mail address: michel.obeid{at}yahoo.fr

³ Abbreviations used in this paper: CRT, calreticulin; BM, bone marrow; DC, dendritic cell; ecto, cell surface; endo, intracellular; ER, endoplasmic reticulum; GADD34, growth arrest and DNA damage inducible protein 34; PP1, protein phosphatase 1; siRNA, small interfering RNA; z-VAD-fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone.

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