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.

摘要

雷帕霉素复合物 1 (TORC1) 的靶标促进细胞合成代谢并抑制巨自噬/自噬。在缺乏氨基酸的哺乳动物细胞中，TORC1 的负调节因子 GATOR1 复合物从其抑制剂 GATOR2 中释放出来，使 TORC1 失活。我们最近在裂变酵母中发现了进化上保守的 GATOR2 成分，包括 Sea3，哺乳动物 WDR59 的直系同源物，但出乎意料的是，Sea3 作为 GATOR1 的一部分来抑制 TORC1。此外，裂殖酵母 GATOR1 不是氨基酸饥饿诱导的 TORC1 衰减所必需的，而是由 Gcn2 途径介导的。相反，缺乏氮源以依赖于 GATOR1 以及 Tsc1-Tsc2 复合物的方式抑制 TORC1，其哺乳动物等效物作为生长因子敏感的 TORC1 抑制剂。因此，