Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan.
Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan.
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DOI：
10.7554/elife.35551
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发表时间：
2018-08-17
期刊：
影响因子：
7.7
通讯作者：
Tyler JK
中科院分区：
文献类型：
--
作者：
Hu Z;Xia B;Postnikoff SD;Shen ZJ;Tomoiaga AS;Harkness TA;Seol JH;Li W;Chen K;Tyler JK
翻译效率与寿命相关，但其在寿命决定中的作用尚不清楚。利用核糖体分析，在芽殖酵母的复制老化过程中，翻译效率至少通过两种机制全面降低：首先，Ssd1在老化过程中被诱导，将mrna隔离到p体上。此外，年轻细胞中Ssd1的过表达减少了翻译，延长了寿命，而年老细胞中Ssd1的缺失减少了翻译缺陷，缩短了寿命。其次，由应激激酶Gcn2介导的eIF2α的磷酸化在老年细胞中升高，在没有检测到下游Gcn4转录激活因子诱导的情况下，导致翻译的全局减少。tRNA过表达激活了年轻细胞中的Gcn2，并以依赖于Gcn4的方式延长寿命。此外，Gcn4的过表达足以在不改变全局翻译的情况下以自噬依赖的方式延长寿命，这表明Gcn4介导的自噬诱导是激活Gcn2延长寿命的最终下游目标。
Translational efficiency correlates with longevity, yet its role in lifespan determination remains unclear. Using ribosome profiling, translation efficiency is globally reduced during replicative aging in budding yeast by at least two mechanisms: Firstly, Ssd1 is induced during aging, sequestering mRNAs to P-bodies. Furthermore, Ssd1 overexpression in young cells reduced translation and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, phosphorylation of eIF2α, mediated by the stress kinase Gcn2, was elevated in old cells, contributing to the global reduction in translation without detectable induction of the downstream Gcn4 transcriptional activator. tRNA overexpression activated Gcn2 in young cells and extended lifespan in a manner dependent on Gcn4. Moreover, overexpression of Gcn4 sufficed to extend lifespan in an autophagy-dependent manner in the absence of changes in global translation, indicating that Gcn4-mediated autophagy induction is the ultimate downstream target of activated Gcn2, to extend lifespan.