The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death

T. Panaretakis, N. Joza, N. Modjtahedi, A. Tesniere, I. Vitale, M. Durchschlag, G. M. Fimia, O. Kepp, M. Piacentini, K. U. Froehlich, P. van Endert, L. Zitvogel, F. Madeo, G. Kroemer

Research output: Contribution to journalArticle

Abstract

The exposure of calreticulin (CRT) on the plasma membrane can precede anthracycline-induced apoptosis and is required for cell death to be perceived as immunogenic. Mass spectroscopy, immunofluorescence and immunoprecipitation experiments revealed that CRT co-translocates to the surface with another endoplasmic reticulum-sessile protein, the disulfide isomerase ERp57. The knockout and knockdown of CRT or ERp57 inhibited the anthracycline-induced translocation of ERp57 or CRT, respectively. CRT point mutants that fail to interact with ERp57 were unable to restore ERp57 translocation upon transfection into crt-/- cells, underscoring that a direct interaction between CRT and ERp57 is strictly required for their co-translocation to the surface. ERp57low tumor cells generated by retroviral introduction of an ERp57-specific shRNA exhibited a normal apoptotic response to anthracyclines in vitro, yet were resistant to anthracycline treatment in vivo. Moreover, ERp57low cancer cells (which failed to expose CRT) treated with anthracyclines were unable to elicit an anti-tumor response in conditions in which control cells were highly immunogenic. The failure of ERp57low cells to elicit immune responses and to respond to chemotherapy could be overcome by exogenous supply of recombinant CRT protein. These results indicate that tumors that possess an intrinsic defect in the CRT-translocating machinery become resistant to anthracycline chemotherapy due to their incapacity to elicit an anti-cancer immune response.

Original languageEnglish
Pages (from-to)1499-1509
Number of pages11
JournalCell Death and Differentiation
Volume15
Issue number9
DOIs
Publication statusPublished - 2008

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Calreticulin
Cell Death
Anthracyclines
Neoplasms
Protein Disulfide-Isomerases
Drug Therapy
Immunoprecipitation
Recombinant Proteins
Endoplasmic Reticulum
Small Interfering RNA
Fluorescent Antibody Technique
Transfection
Mass Spectrometry
Cell Membrane
Apoptosis

ASJC Scopus subject areas

  • Cell Biology

Cite this

Panaretakis, T., Joza, N., Modjtahedi, N., Tesniere, A., Vitale, I., Durchschlag, M., ... Kroemer, G. (2008). The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death and Differentiation, 15(9), 1499-1509. https://doi.org/10.1038/cdd.2008.67

The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. / Panaretakis, T.; Joza, N.; Modjtahedi, N.; Tesniere, A.; Vitale, I.; Durchschlag, M.; Fimia, G. M.; Kepp, O.; Piacentini, M.; Froehlich, K. U.; van Endert, P.; Zitvogel, L.; Madeo, F.; Kroemer, G.

In: Cell Death and Differentiation, Vol. 15, No. 9, 2008, p. 1499-1509.

Research output: Contribution to journalArticle

Panaretakis, T, Joza, N, Modjtahedi, N, Tesniere, A, Vitale, I, Durchschlag, M, Fimia, GM, Kepp, O, Piacentini, M, Froehlich, KU, van Endert, P, Zitvogel, L, Madeo, F & Kroemer, G 2008, 'The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death', Cell Death and Differentiation, vol. 15, no. 9, pp. 1499-1509. https://doi.org/10.1038/cdd.2008.67
Panaretakis, T. ; Joza, N. ; Modjtahedi, N. ; Tesniere, A. ; Vitale, I. ; Durchschlag, M. ; Fimia, G. M. ; Kepp, O. ; Piacentini, M. ; Froehlich, K. U. ; van Endert, P. ; Zitvogel, L. ; Madeo, F. ; Kroemer, G. / The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. In: Cell Death and Differentiation. 2008 ; Vol. 15, No. 9. pp. 1499-1509.
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