Translocational attenuation mediated by the PERK-SRP14 axis is a protective mechanism of unfolded protein response

Yaofu Liu, Yuexi Gu, Ying Chen, Xuan Wang, Guangfeng Zhou, Jing Li, Mu Wang*, Shengyun Fang*, Yili Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The unfolded protein response (UPR) relieves endoplasmic reticulum (ER) stress through multiple strategies, including reducing protein synthesis, increasing protein folding capabilities, and enhancing misfolded protein degradation. After a multi-omics analysis, we find that signal recognition particle 14 (SRP14), an essential component of the SRP, is markedly reduced in cells undergoing ER stress. Further experiments indicate that SRP14 reduction requires PRKR-like ER kinase (PERK)-mediated eukaryotic translation initiation factor 2α (eIF2α) phosphorylation but is independent of ATF4 or ATF3 transcription factors. The decrease of SRP14 correlates with reduced translocation of fusion proteins and endogenous cathepsin D. Enforced expression of an SRP14 variant with elongation arrest capability prevents the reduced translocation of cathepsin D in stressed cells, whereas an SRP14 mutant without the activity does not. Finally, overexpression of SRP14 augments the UPR and aggravates ER-stress-induced cell death. These data suggest that translocational attenuation mediated by the PERK-SRP14 axis is a protective measure for the UPR to mitigate ER stress.

Original languageEnglish
Article number114402
JournalCell Reports
Volume43
Issue number7
DOIs
Publication statusPublished - 23 Jul 2024

Keywords

  • cathepsin D
  • CP: Molecular biology
  • ER stress
  • PERK-eIF2α
  • signal peptide
  • signal recognition particle
  • SRP14
  • translocational attenuation
  • UPR

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