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Mechanisms of pre‐apoptotic calreticulin exposure in immunogenic cell death
Author(s) -
Panaretakis Theocharis,
Kepp Oliver,
Brockmeier Ulf,
Tesniere Antoine,
Bjorklund AnnCharlotte,
Chapman Daniel C,
Durchschlag Michael,
Joza Nicholas,
Pierron Gérard,
van Endert Peter,
Yuan Junying,
Zitvogel Laurence,
Madeo Frank,
Williams David B,
Kroemer Guido
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.1
Subject(s) - calreticulin , biology , immunogenic cell death , endoplasmic reticulum , microbiology and biotechnology , programmed cell death , caspase 12 , unfolded protein response , apoptosis , caspase , kinase , biochemistry
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 eIF2α, 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 eIF2α (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.