An evolutionarily conserved pathway controls proteasome homeostasis.
An evolutionarily conserved pathway controls proteasome homeostasis.
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DOI：
10.1038/nature18943
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发表时间：
2016-08-11
期刊：
影响因子：
64.8
通讯作者：
Bertolotti A
中科院分区：
文献类型：
--
作者：
Rousseau A;Bertolotti A
蛋白酶体对于大多数细胞蛋白质的选择性降解是必不可少的，但是细胞如何保持足够量的蛋白酶体尚不清楚。在这里，我们发现了一个进化保守的信号通路控制蛋白酶体的稳态。该途径的中心是TORC 1，其抑制诱导所有已知的酵母19 S调节颗粒组装-伴侣蛋白（RAC）以及蛋白酶体亚基。在TORC 1抑制的下游，酵母促分裂原活化蛋白激酶Mpk 1确保了RAC和蛋白酶体亚基的供应在挑战性条件下增加，以维持蛋白酶体降解和细胞活力。这种适应性途径在进化上是保守的，mTOR和Erk 5控制着四种哺乳动物RAC的水平和蛋白酶体丰度。因此，中央生长和应激控制器TORC 1和Mpk 1/Erk 5赋予细胞快速和重要的适应性反应，以调整蛋白酶体丰度以满足不断增长的需求。增强这一途径可能是一个有用的治疗方法，由受损的蛋白酶体降解引起的疾病。
The proteasome is essential for the selective degradation of most cellular proteins but how cells maintain adequate amounts of proteasome is unclear. Here we found an evolutionarily conserved signalling pathway controlling proteasome homeostasis. Central to this pathway is TORC1 whose inhibition induced all known yeast 19S regulatory particle assembly-chaperones (RACs) as well as proteasome subunits. Downstream of TORC1 inhibition, the yeast mitogen-activated protein kinase, Mpk1, ensured that the supply of RACs and proteasome subunits increased under challenging conditions to maintain proteasomal degradation and cell viability. This adaptive pathway was evolutionarily conserved, with mTOR and Erk5 controlling the levels of the four mammalian RACs and proteasome abundance. Thus, the central growth and stress controllers, TORC1 and Mpk1/Erk5, endow cells with a rapid and vital adaptive response to adjust proteasome abundance to the rising needs. Enhancing this pathway may be a useful therapeutic approach for diseases resulting from impaired proteasomal degradation.