Disruption of the PP1/GADD34 complex induces calreticulin exposure

Oliver Kepp, Lorenzo Galluzzi, Fabrizio Giordanetto, Antoine Tesniere, Ilio Vitale, Isabelle Martins, Frederic Schlemmer, Sandy Adjemian, Laurence Zitvogel, Guido Kroemer

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

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    Résumé

    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.

    langue originaleAnglais
    Pages (de - à)3971-3977
    Nombre de pages7
    journalCell Cycle
    Volume8
    Numéro de publication23
    Les DOIs
    étatPublié - 1 déc. 2009

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