Disruption of the PP1/GADD34 complex induces calreticulin exposure

作者：Kepp Oliver; Galluzzi Lorenzo; Giordanetto Fabrizio; Tesniere Antoine; Vitale Ilio; Martins Isabelle; Schlemmer Frederic; Adjemian Sandy; Zitvogel Laurence; Kroemer Guido^*

来源：Cell Cycle, 2009, 8(23): 3971-3977.

DOI：10.4161/cc.8.23.10191

• cancer chemotherapy
• cervical carcinoma
• immunogenic cell death
• PERK
• PPP1R15A
• small peptide inhibitor

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 2 alpha (eIF2 alpha) by the eIF2 alpha kinase PERK, yet may also be triggered by inhibition of the eIF2 alpha phosphatase, which is composed by a catalytic subunit (PP 1) 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 PP 1 and GADD34, stimulated the phosphorylation of eIF2 alpha, 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.

• 出版日期2009-12-1