Proteostasis in dendritic cells is controlled by the PERK signaling axis independently of ATF4

Life Sci Alliance. 2020 Dec 21;4(2):e202000865. doi: 10.26508/lsa.202000865. Print 2021 Feb.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry
  • Actins / metabolism
  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Antigens / immunology
  • Cell Movement / genetics
  • Cytokines
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Gene Knockdown Techniques
  • Lipopolysaccharides / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Phosphorylation
  • Protein Multimerization
  • Proteostasis*
  • Signal Transduction*
  • Spleen / metabolism
  • Subtilisins / metabolism
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism*

Substances

  • Actins
  • Antigens
  • Cytokines
  • Lipopolysaccharides
  • Membrane Proteins
  • flt3 ligand protein
  • Activating Transcription Factor 4
  • PERK kinase
  • eIF-2 Kinase
  • Subtilisins