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
Affiliations
Yaofu Liu
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
Yuexi Gu
China Regional Research Centre, International Centre for Genetic Engineering and Biotechnology (ICGEB), Taizhou, Jiangsu 225316, China
Ying Chen
Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, China
Xuan Wang
China Regional Research Centre, International Centre for Genetic Engineering and Biotechnology (ICGEB), Taizhou, Jiangsu 225316, China
Guangfeng Zhou
China Regional Research Centre, International Centre for Genetic Engineering and Biotechnology (ICGEB), Taizhou, Jiangsu 225316, China
Jing Li
Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, China
Mu Wang
Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, Jiangsu 215123, China; Corresponding author
Shengyun Fang
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; Corresponding author
Yili Yang
China Regional Research Centre, International Centre for Genetic Engineering and Biotechnology (ICGEB), Taizhou, Jiangsu 225316, China; Corresponding author
Summary: 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.