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.
摘要：
未折叠蛋白反应（UPR）通过多种策略缓解内质网（ER）应激，包括减少蛋白质合成,增加蛋白质折叠能力，并增强错误折叠的蛋白质降解。经过多组学分析,我们发现信号识别粒子14(SRP14)，SRP的重要组成部分，在经历内质网应激的细胞中显著减少。进一步的实验表明，SRP14的减少需要PRKR样ER激酶（PERK）介导的真核翻译起始因子2α（eIF2α）磷酸化，但与ATF4或ATF3转录因子无关。SRP14的减少与融合蛋白和内源性组织蛋白酶D的易位减少相关。具有延伸阻滞能力的SRP14变体的强制表达可防止组织蛋白酶D在应激细胞中的易位减少。而没有活性的SRP14突变体则没有。最后,SRP14的过表达增加了UPR并加重了ER应激诱导的细胞死亡。这些数据表明由PERK-SRP14轴介导的转位衰减是UPR减轻ER应激的保护性措施。
