1. Academic Validation
  2. Translocational attenuation mediated by the PERK-SRP14 axis is a protective mechanism of unfolded protein response

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

  • Cell Rep. 2024 Jul 23;43(7):114402. doi: 10.1016/j.celrep.2024.114402.
Yaofu Liu 1 Yuexi Gu 2 Ying Chen 3 Xuan Wang 2 Guangfeng Zhou 2 Jing Li 3 Mu Wang 4 Shengyun Fang 5 Yili Yang 6
Affiliations

Affiliations

  • 1 China Regional Research Centre, International Centre for Genetic Engineering and Biotechnology (ICGEB), Taizhou, Jiangsu 225316, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China; Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 China Regional Research Centre, International Centre for Genetic Engineering and Biotechnology (ICGEB), Taizhou, Jiangsu 225316, China.
  • 3 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, China.
  • 4 Academy of Pharmacy, Xi'an Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, China. Electronic address: mu.wang@xjtlu.edu.cn.
  • 5 Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: sfang@som.umaryland.edu.
  • 6 China Regional Research Centre, International Centre for Genetic Engineering and Biotechnology (ICGEB), Taizhou, Jiangsu 225316, China. Electronic address: nathanyang@icgeb.cn.
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.

Keywords

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

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