INSERM, U848, Villejuif, France.
Cell Cycle. 2009 Dec;8(23):3971-7. doi: 10.4161/cc.8.23.10191. Epub 2009 Dec 28.
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 2alpha(eIF2alpha) by the eIF2alpha kinase PERK, yet may also be triggered by inhibition of the eIF2alpha 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 eIF2alpha, 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.
针对某些化疗药物，肿瘤细胞可以将钙网蛋白（CRT）从内质网腔转移到质膜表面。这种效应需要真核起始因子 2α(eIF2α)激酶 PERK 对 eIF2α 的磷酸化，但也可能被由催化亚基（PP1）和调节亚基（GADD34）组成的 eIF2α 磷酸酶抑制所触发。在这里，我们提出了一个问题，即 PP1/GADD34 复合物的解离是否足以触发 CRT 暴露。分子建模导致了设计一种 GADD34 衍生肽，该肽可竞争性地破坏 PP1/GADD34 复合物。当添加到完整细胞时，与质膜转位结构域融合的 GADD34 衍生肽会破坏 PP1 和 GADD34 之间的相互作用，刺激 eIF2α 的磷酸化，并触发 CRT 暴露。然而，PP1/GADD34 复合物的解析并没有引发细胞凋亡，允许 CRT 暴露和细胞死亡的分离。蒽环类抗生素在诱导 CRT 易位到细胞表面方面非常有效，也能刺激 PP1/GADD34 复合物的解离。这些结果表明，PP1/GADD34 复合物在 CRT 暴露的调节中起着重要作用。
