ERP57 membrane translocation dictates the immunogenicity of tumor cell death by controlling the membrane translocation of calreticulin.
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.
Obeid
Michel
M
GenCal, Paris, France. michel.obeid@yahoo.fr
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D037282:Calreticulin / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008942:Mitoxantrone / Q000008:administration & dosage; D009368:Neoplasm Transplantation; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D019704:Protein Disulfide-Isomerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D037282:Calreticulin; D034741:RNA, Small Interfering; D008942:Mitoxantrone; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases