Cattie Douglas J, Richardson Claire E, Reddy Kirthi C, Ness-Cohn Elan M, Droste Rita, Thompson Mary K, Gilbert Wendy V, Kim Dennis H
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
Howard Hughes Medical Institute, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
PLoS Genet. 2016 Sep 30;12(9):e1006326. doi: 10.1371/journal.pgen.1006326. eCollection 2016 Sep.
The translation initiation factor eIF3 is a multi-subunit protein complex that coordinates the assembly of the 43S pre-initiation complex in eukaryotes. Prior studies have demonstrated that not all subunits of eIF3 are essential for the initiation of translation, suggesting that some subunits may serve regulatory roles. Here, we show that loss-of-function mutations in the genes encoding the conserved eIF3k and eIF3l subunits of the translation initiation complex eIF3 result in a 40% extension in lifespan and enhanced resistance to endoplasmic reticulum (ER) stress in Caenorhabditis elegans. In contrast to previously described mutations in genes encoding translation initiation components that confer lifespan extension in C. elegans, loss-of-function mutations in eif-3.K or eif-3.L are viable, and mutants show normal rates of growth and development, and have wild-type levels of bulk protein synthesis. Lifespan extension resulting from EIF-3.K or EIF-3.L deficiency is suppressed by a mutation in the Forkhead family transcription factor DAF-16. Mutations in eif-3.K or eif-3.L also confer enhanced resistance to ER stress, independent of IRE-1-XBP-1, ATF-6, and PEK-1, and independent of DAF-16. Our data suggest a pivotal functional role for conserved eIF3k and eIF3l accessory subunits of eIF3 in the regulation of cellular and organismal responses to ER stress and aging.
翻译起始因子eIF3是一种多亚基蛋白质复合物，它在真核生物中协调43S起始前复合物的组装。先前的研究表明，并非eIF3的所有亚基对于翻译起始都是必需的，这表明一些亚基可能发挥调节作用。在此，我们表明，翻译起始复合物eIF3的保守亚基eIF3k和eIF3l的编码基因中的功能丧失突变导致秀丽隐杆线虫的寿命延长40%，并增强了对内质网（ER）应激的抗性。与先前描述的在秀丽隐杆线虫中赋予寿命延长的翻译起始成分编码基因中的突变不同，eif-3.K或eif-3.L中的功能丧失突变是可行的，突变体显示出正常的生长和发育速率，并且具有野生型水平的整体蛋白质合成。由EIF-3.K或EIF-3.L缺陷导致的寿命延长被叉头家族转录因子DAF-16中的突变所抑制。eif-3.K或eif-3.L中的突变还赋予对ER应激的增强抗性，这独立于IRE-1-XBP-1、ATF-6和PEK-1，并且独立于DAF-16。我们的数据表明，eIF3的保守辅助亚基eIF3k和eIF3l在调节细胞和生物体对内质网应激和衰老的反应中起关键功能作用。
