Abstract
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.
Highlights
DCs are key regulators of both protective immune responses and tolerance to self-antigens (Dalod et al, 2014)
We found that mRNA translation in DCs, differently to what has been shown during chronic integrated stress response (ISR) (Guan et al, 2017), is mediated despite high p-eukaryotic initiation factor 2α (eIF2α) levels by an eIF4F-dependent mechanism
We have previously proposed the existence of a strong causative link between cell activation by TLR ligands and eIF2α phosphorylation, notably by virtue of strong GADD34 expression in most transcriptomics studies performed on PAMP-activated DCs (Clavarino et al, 2012b; Claudio et al, 2013; Reverendo et al, 2018)
Summary
DCs are key regulators of both protective immune responses and tolerance to self-antigens (Dalod et al, 2014). LPS detection by TLR4 promotes DCs maturation by triggering a series of signaling cascades resulting in secretion of polarizing and inflammatory cytokines, up-regulation of co-stimulatory molecules, as well as enhanced antigen processing and presentation (Mellman, 2013). All these functions are accompanied by major remodeling of membrane trafficking and actin organization to favor both antigen capture and migration to the lymph nodes (West et al, 2004; Chabaud et al, 2015; Arguello et al, 2016; Bretou et al, 2017). Increased eIF2α phosphorylation impacts cells in two main ways: (i) By reducing the rate of translation initiation and global protein synthesis levels; (ii) By favoring the translation of the activating transcription factor 4 (ATF4) (Han et al, 2013; Fusakio et al, 2016) which in turn activates the transcription of genes involved in the integrated stress response (ISR) (Costa-Mattioli & Walter, 2020)
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