Phylogenetic conservation of the preapoptotic calreticulin exposure pathway from yeast to mammals.
The pre-apoptotic exposure of calreticulin (CRT) on the cell surface determines the efficient engulfment of mouse or human tumor cells by antigen-presenting dendritic cells. CRT exposure is rapidly induced by anthracyclins and ionizing irradiation and follows a complex signal transduction pathway that is interrupted by depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs, as well as by knock-in mutation of eIF2alpha (to make it non-phosphorylable by PERK) or BAP31 (to render it uncleavable by caspase-8). Here, we show that yeast (Saccharomyces cerevisiae) can expose the CRT orthologue CNE1 on the surface in response to cell death induced by the anthracylin mitoxantrone (MTX). This MTX-triggered CNE1 translocation is abolished by knockout of the yeast orthologues of PERK (Gcn2), BAP31 (Yet3) and SNAREs (Nyv1, Sso1). Altogether, our data point to the existence of an ancestral and cell death-related CRT exposure pathway with conserved elements shared between unicellular fungi and mammals.
Madeo
Frank
F
Institute of Molecular Biosciences, University of Graz, Graz, Austria.
Durchschlag
Michael
M
Kepp
Oliver
O
Panaretakis
Theocharis
T
Zitvogel
Laurence
L
Fröhlich
Kai-Uwe
KU
Kroemer
Guido
G
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D037281:Calnexin / Q000235:genetics / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008942:Mitoxantrone / Q000378:metabolism; D010802:Phylogeny; D021381:Protein Transport / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D000970:Antineoplastic Agents; C091247:BCAP31 protein, human; C080582:CNE1 protein, S cerevisiae; D037282:Calreticulin; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D037281:Calnexin; D008942:Mitoxantrone