title: Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death.
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 eIF2alpha, 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 eIF2alpha (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.
authors.affiliation: INSERM, Unit 848, Villejuif, France.
authors.forename: Theocharis
authors.initials: T
authors.lastname: Panaretakis
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.forename: Ulf
authors.initials: U
authors.lastname: Brockmeier
authors.forename: Antoine
authors.initials: A
authors.lastname: Tesniere
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Bjorklund
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chapman
authors.forename: Michael
authors.initials: M
authors.lastname: Durchschlag
authors.forename: Nicholas
authors.initials: N
authors.lastname: Joza
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.forename: David B
authors.initials: DB
authors.lastname: Williams
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D018943:Anthracyclines / Q000276:immunology / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis; D037282:Calreticulin / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000276:immunology*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005089:Exocytosis; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000276:immunology / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation; D050600:SNARE Proteins / Q000378:metabolism; D014466:Ultraviolet Rays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D037282:Calreticulin; D053148:Caspase 3; D053181:Caspase 8; D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D050600:SNARE Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase; C494772:BAK1 protein, human; C494826:BAX protein, human; C091247:BCAP31 protein, human