Developmentally regulated PERK activity renders dendritic cells insensitive to subtilase cytotoxin-induced integrated stress response

Pierre, P.; Mendes, A.; Gigan, J. P.; Rodriguez Rodrigues, C.; Choteau, S. A.; Sanseau, D.; Barros, D.; Almeida, C.; Camosseto, V.; Chasson, L.; Paton, A. W.; Paton, J. C.; Argüello, R. J.; Lennon-Dumenil, A.-M.; Gatti, E.

doi:10.1101/2020.04.27.063438

bioRxiv · 10.1101/2020.04.27.063438

Developmentally regulated PERK activity renders dendritic cells insensitive to subtilase cytotoxin-induced integrated stress response

Pierre, P.·Mendes, A.·Gigan, J. P.·Rodriguez Rodrigues, C.·Choteau, S. A.·Sanseau, D.·Barros, D.·Almeida, C.·Camosseto, V.·Chasson, L.·Paton, A. W.·Paton, J. C.·Argüello, R. J.·Lennon-Dumenil, A.-M.·Gatti, E.

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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 (ISR). We show here that dendritic cells (DCs) display unusually high eIF2 phosphorylation, which is mostly caused by a developmentally regulated activation of the ER kinase PERK (EIF2AK3). Despite high p-eIF2 levels, differentiated DCs display active protein synthesis and no signs of a chronic ISR. eIF2 phosphorylation does not majorly impact DC differentiation nor cytokines production. It is however important to adapt protein homeostasis to the variations imposed on DCs by the immune or physiological contexts. This biochemical specificity prevents translation arrest and expression of the transcription factor ATF4 during ER-stress induction by subtilase cytotoxin or upon DC stimulation with bacterial lipopolysaccharides. This is also exemplified by the influence of the actin cytoskeleton dynamics on eIF2 phosphorylation and the migratory deficit observed in PERK-deficient DCs.

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Pierre, P., Mendes, A., Gigan, J. P., Rodriguez Rodrigues, C., Choteau, S. A., Sanseau, D., Barros, D., Almeida, C., Camosseto, V., Chasson, L., Paton, A. W., Paton, J. C., Argüello, R. J., Lennon-Dumenil, A.-M., Gatti, E.. 2020-04-29. Developmentally regulated PERK activity renders dendritic cells insensitive to subtilase cytotoxin-induced integrated stress response. https://doi.org/10.1101/2020.04.27.063438

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