Article
- The EMBO Journal (2009) 28, 578 - 590
- doi:10.1038/emboj.2009.1
Published online: 22 January 2009
Subject Category:
Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death
Theocharis Panaretakis1,2,3,a, Oliver Kepp1,2,3,a, Ulf Brockmeier4,a, Antoine Tesniere1,2,3, Ann-Charlotte Bjorklund5, Daniel C Chapman4, Michael Durchschlag6, Nicholas Joza1,2,3, Gérard Pierron7, Peter van Endert8,9, Junying Yuan10, Laurence Zitvogel2,3,11, Frank Madeo6, David B Williams4 and Guido Kroemer1,2,3
- INSERM, Unit 848, Villejuif, France
- Institut Gustave Roussy, Villejuif, France
- Université Paris Sud, Paris 11, Villejuif, France
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
- CancerCentrum Karolinska, Karolinska Institute, Stockholm, Sweden
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
- CNRS, FRE 2937, Institut Andre Lwoff, Villejuif, France
- INSERM, U580, Paris, France
- Faculté de Médecine René Descartes, Université Paris-Descartes, Paris, France
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA
- INSERM, U805, Institut Gustave Roussy, Villejuif, France
Correspondence to:
Guido Kroemer, INSERM, U848, Institut Gustave Roussy, PR1, 39, rue Camille Desmoulins, 94805 Villejuif, France. Tel.: +33 1 42 11 60 46; Fax: +33 1 42 11 60 47; E-mail: kroemer@igr.fr
aThese authors contributed equally to this work
Received 27 June 2008; Accepted 29 December 2008
Abstract
Dying tumour cells can elicit a potent anticancer immune response by exposing the calreticulin (CRT)/ERp57 complex on the cell surface before the cells manifest any signs of apoptosis. Here, we enumerate elements of the pathway that mediates pre-apoptotic CRT/ERp57 exposure in response to several immunogenic anticancer agents. Early activation of the endoplasmic reticulum (ER)-sessile kinase PERK leads to phosphorylation of the translation initiation factor eIF2
, followed by partial activation of caspase-8 (but not caspase-3), caspase-8-mediated cleavage of the ER protein BAP31 and conformational activation of Bax and Bak. Finally, a pool of CRT that has transited the Golgi apparatus is secreted by SNARE-dependent exocytosis. Knock-in mutation of eIF2 (to make it non-phosphorylatable) or BAP31 (to render it uncleavable), depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs abolished CRT/ERp57 exposure induced by anthracyclines, oxaliplatin and ultraviolet C light. Depletion of PERK, caspase-8 or SNAREs had no effect on cell death induced by anthracyclines, yet abolished the immunogenicity of cell death, which could be restored by absorbing recombinant CRT to the cell surface.
Keywords:
- calreticulin,
- caspase,
- endoplasmic reticulum stress,
- ERp57,
- exocytosis
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