Journal
EMBO JOURNAL
Volume 28, Issue 5, Pages 578-590Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2009.1
Keywords
calreticulin; caspase; endoplasmic reticulum stress; ERp57; exocytosis
Categories
Funding
- Ligue Nationale contre le Cancer (Equipe labellisee)
- European Commission
- Canceropole Ile-de-France
- Fondation de France and Fondation pour la Recherche Medicale
- Swedish Research Council (Vetenskapsra det)
- Poste d'accueil INSERM
- EMBO
- CIHR Training Program in the Structural Biology of Membrane Proteins Linked to Disease
- CIHR and Canadian Cancer Society
- Fonds zur Forderung der wissenschaftlichen Forschung (Austria)
- Fonds zur Forderung der wissenschaftlichen Forschung (Austria) [S-9304-B05]
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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 alpha, 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 alpha (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.
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