TY - JOUR
T1 - Disruption of the PP1/GADD34 complex induces calreticulin exposure
AU - Kepp, Oliver
AU - Galluzzi, Lorenzo
AU - Giordanetto, Fabrizio
AU - Tesniere, Antoine
AU - Vitale, Ilio
AU - Martins, Isabelle
AU - Schlemmer, Frederic
AU - Adjemian, Sandy
AU - Zitvogel, Laurence
AU - Kroemer, Guido
N1 - Funding Information:
G.K. is supported by the Ligue Nationale contre le Cancer (Equipes labellisée), Agence Nationale pour la Recherche (ANR), European Commission (Apo-Sys, ChemoRes, ApopTrain), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa) and Cancéropôle Ile-de-France. O.K. receives a post-doctoral fellowship from EMBO, L.G. is supported by Apo-Sys, I.M. by the Ligue Nationale contre le Cancer, L.S. and M.M. by FRM fellowships.
PY - 2009/12/1
Y1 - 2009/12/1
N2 - In response to some chemotherapeutic agents, tumor cells can translocate calreticulin (CRT), which is usually contained in the lumen of the endoplasmic reticulum, to the surface of the plasma membrane. This effect requires the phosphorylation of the eukaryotic initiation factor 2α (eIF2α) by the eIF2α kinase PE RK, yet may also be triggered by inhibition of the eIF2α phosphatase, which is composed by a catalytic subunit (PP1) and a regulatory subunit (GADD34). Here, we addressed the question whether the dissociation of the PP1/GADD34 complex would be sufficient to trigger CRT exposure. Molecular modeling led to the design of a GADD34-derived peptide that competitively disrupts the PP1/GADD34 complex. When added to intact cells, the GADD34-derived peptide fused to a plasma membrane translocation domain abolished the interaction between PP1 and GADD34, stimulated the phosphorylation of eIF2α, and triggered CRT exposure. However, the resolution of the PP1/GADD34 complex did not evoke apoptosis, allowing for the dissociation of CRT exposure and cell death. Anthracyclins, which are highly efficient in inducing CRT translocation to the cell surface also stimulated the dissociation of the PP1/GADD34 complex. These results suggest that the PP1/GADD34 complex plays a major role in the regulation of CRT exposure.
AB - In response to some chemotherapeutic agents, tumor cells can translocate calreticulin (CRT), which is usually contained in the lumen of the endoplasmic reticulum, to the surface of the plasma membrane. This effect requires the phosphorylation of the eukaryotic initiation factor 2α (eIF2α) by the eIF2α kinase PE RK, yet may also be triggered by inhibition of the eIF2α phosphatase, which is composed by a catalytic subunit (PP1) and a regulatory subunit (GADD34). Here, we addressed the question whether the dissociation of the PP1/GADD34 complex would be sufficient to trigger CRT exposure. Molecular modeling led to the design of a GADD34-derived peptide that competitively disrupts the PP1/GADD34 complex. When added to intact cells, the GADD34-derived peptide fused to a plasma membrane translocation domain abolished the interaction between PP1 and GADD34, stimulated the phosphorylation of eIF2α, and triggered CRT exposure. However, the resolution of the PP1/GADD34 complex did not evoke apoptosis, allowing for the dissociation of CRT exposure and cell death. Anthracyclins, which are highly efficient in inducing CRT translocation to the cell surface also stimulated the dissociation of the PP1/GADD34 complex. These results suggest that the PP1/GADD34 complex plays a major role in the regulation of CRT exposure.
KW - Cancer chemotherapy
KW - Cervical carcinoma
KW - Immunogenic cell death
KW - PERK
KW - PPP1R15A
KW - Small peptide inhibitor
UR - http://www.scopus.com/inward/record.url?scp=74849124789&partnerID=8YFLogxK
U2 - 10.4161/cc.8.23.10191
DO - 10.4161/cc.8.23.10191
M3 - Article
AN - SCOPUS:74849124789
SN - 1538-4101
VL - 8
SP - 3971
EP - 3977
JO - Cell Cycle
JF - Cell Cycle
IS - 23
ER -