Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death.
EMBO J
; 28(5): 578-90, 2009 Mar 04.
Article
em En
| MEDLINE
| ID: mdl-19165151
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Morte Celular
/
Calreticulina
/
Retículo Endoplasmático
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
EMBO J
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
França