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

ABSTRACT: In stressed cells, phosphorylation of eukaryotic initiation factor 2? (eIF2?) 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 eIF2? phosphorylation, mostly caused by the activation of the ER kinase PERK (EIF2AK3). Despite high p-eIF2? 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-? 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 eIF2? phosphorylation is likely important to adapt DC homeostasis to the variations imposed by the immune contexts.

SUBMITTER: Mendes A

PROVIDER: S-EPMC7756897 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Mendes Andreia A Gigan Julien P JP Rodriguez Rodrigues Christian C Choteau Sébastien A SA Sanseau Doriane D Barros Daniela D Almeida Catarina C Camosseto Voahirana V Chasson Lionel L Paton Adrienne W AW Paton James C JC Argüello Rafael J RJ Lennon-Duménil Ana-Maria AM Gatti Evelina E Pierre Philippe P

Life science alliance 20201221 2

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 ...[more]

PMID: 33443099

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Project description:Selenite has emerged as an optional chemotherapeutic agent for hematological malignancies. Autophagy and apoptosis are both engaged in selenite-induced cell death. In a previous report, we have identified heat shock protein 90 (Hsp90) as a critical modulator of the balance between autophagy and apoptosis in selenite-treated leukemia cells. However, the mechanisms by which selenite mediates the crosstalk between autophagy and apoptosis remain largely unknown. Herein, we demonstrate that the endoplasmic reticulum (ER) stress-related PERK/eIF2α/ATF4 pathway and p38 are core modules for the selenite-induced switch to apoptosis from autophagy. We found that selenite activated PERK and eIF2α/ATF4 downstream to promote apoptosis. During this progression, p38 was dissociated from PERK-inhibiting Hsp90 and became autophosphorylated. Then, activated p38 further enhanced the docking of activating transcription factor 4 (ATF4) onto the CHOP (CCAAT/enhancer-binding protein homologous protein) promoter via eIF2α to enhance apoptosis. We also found that activated p38 suppressed the phosphorylation of eIF4E that directed ATF4 to bind to the MAP1LC3B (microtubule-associated protein 1 light chain 3B) promoter. Because of the deactivation of eIF4E, the association of ATF4 with the MAP1LC3B promoter was inhibited, and autophagy was compromised. Intriguingly, p53 played important roles in mediating the p38-mediated regulation of eIF2α and eIF4E. When activated by p38, p53 induced the phosphorylation of eIF2α and the dephosphorylation of eIF4E, particularly in the nucleus where the ATF4 transcription factor was modulated, ultimately resulting in differential expression of CHOP and LC3. Moreover, selenite exhibited potent antitumor effects in vivo. In an NB4 cell xenograft model, selenite induced apoptosis and hampered autophagy. In addition, related signaling proteins demonstrated similar changes to those observed in vitro. These data suggest that selenite may be a candidate drug for leukemia therapy.

Dataset Information

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

Publications

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

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