Aix Marseille Université, Centre National de la Recherch Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille Luminy (CIML), CENTURI, Marseille, France.
Department of Medical Sciences, Institute for Research in Biomedicine (iBiMED) and Ilidio Pinho Foundation, University of Aveiro, Aveiro, Portugal.
Life Sci Alliance. 2020 Dec 21;4(2). doi: 10.26508/lsa.202000865. Print 2021 Feb.
In stressed cells, phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation and gene expression known as the integrated stress response. We show here that DCs are characterized by high eIF2α phosphorylation, mostly caused by the activation of the ER kinase PERK (EIF2AK3). Despite high p-eIF2α levels, DCs display active protein synthesis and no signs of a chronic integrated stress response. This biochemical specificity prevents translation arrest and expression of the transcription factor ATF4 during ER-stress induction by the subtilase cytotoxin (SubAB). PERK inactivation, increases globally protein synthesis levels and regulates IFN-β expression, while impairing LPS-stimulated DC migration. Although the loss of PERK activity does not impact DC development, the cross talk existing between actin cytoskeleton dynamics; PERK and eIF2α phosphorylation is likely important to adapt DC homeostasis to the variations imposed by the immune contexts.
在应激细胞中，真核起始因子 2α（eIF2α）的磷酸化控制着 mRNA 翻译和基因表达的全转录组变化，这种变化被称为综合应激反应。我们在这里表明，DC 以高 eIF2α 磷酸化为特征，这主要是由内质网激酶 PERK（EIF2AK3）的激活引起的。尽管 p-eIF2α 水平较高，但 DC 仍显示出活跃的蛋白质合成，没有慢性综合应激反应的迹象。这种生化特异性可防止在 SUBAB（一种枯草溶菌素细胞毒素）诱导内质网应激时翻译受阻和转录因子 ATF4 的表达。PERK 的失活会增加整体蛋白质合成水平并调节 IFN-β 的表达，同时损害 LPS 刺激的 DC 迁移。尽管 PERK 活性的丧失不会影响 DC 的发育，但肌动蛋白细胞骨架动力学、PERK 和 eIF2α 磷酸化之间的相互作用可能对适应 DC 动态平衡至关重要，以适应免疫环境带来的变化。
