Multiplexed suppression of TOR complex 1 induces autophagy during starvation
Multiplexed suppression of TOR complex 1 induces autophagy during starvation
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DOI：
10.1080/15548627.2021.1938915
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发表时间：
2021-06
期刊：
影响因子：
13.3
通讯作者：
Tomoyuki Fukuda;K. Shiozaki
中科院分区：
文献类型：
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作者：
Tomoyuki Fukuda;K. Shiozaki
雷帕霉素复合物靶蛋白1（TORC 1）促进细胞凋亡并抑制大自噬/自噬。在缺乏氨基酸的哺乳动物细胞中，TORC 1的负调节因子GATOR 1复合物从其抑制剂GATOR 2中释放出来，使TORC 1失活。我们最近已经确定了裂变酵母中进化上保守的GATOR 2组分，包括哺乳动物WDR 59的直系同源物Sea 3，但出乎意料的是，Sea 3作为GATOR 1的一部分来抑制TORC 1。此外，裂殖酵母GATOR 1不是氨基酸饥饿诱导的TORC 1衰减所必需的，而是由Gcn 2途径介导的。相反，缺乏氮源抑制TORC 1的方式依赖于GATOR 1以及Tsc 1-Tsc 2复合物，其哺乳动物等效功能作为生长因子敏感的TORC 1抑制剂。因此，进化上保守的信号传导模块在裂殖酵母和哺乳动物之间被不同地利用以控制TORC 1活性和自噬。
ABSTRACT Target of rapamycin complex 1 (TORC1) promotes cellular anabolism and suppresses macroautophagy/autophagy. In mammalian cells starved of amino acid, the GATOR1 complex, a negative regulator of TORC1, is released from its inhibitor GATOR2 and inactivates TORC1. We have recently identified the evolutionarily conserved GATOR2 components in fission yeast including Sea3, an ortholog of mammalian WDR59, but, unexpectedly, Sea3 acts as a part of GATOR1 to suppress TORC1. Moreover, fission yeast GATOR1 is not required for the amino-acid starvation-induced TORC1 attenuation, which is instead mediated by the Gcn2 pathway. Conversely, absence of a nitrogen source suppresses TORC1 in a manner dependent on GATOR1 as well as the Tsc1-Tsc2 complex, whose mammalian equivalent functions as a growth-factor sensitive TORC1 inhibitor. Thus, the evolutionarily conserved signaling modules are utilized differently between fission yeast and mammals to control TORC1 activity and autophagy.