Tripartite suppression of fission yeast TORC1 signaling by the GATOR1-Sea3 complex, the TSC complex, and Gcn2 kinase.
Tripartite suppression of fission yeast TORC1 signaling by the GATOR1-Sea3 complex, the TSC complex, and Gcn2 kinase.
复制标题
Gator1-SEA3复合物，TSC复合物和GCN2激酶对裂变酵母Torc1信号的三方抑制。
DOI：
10.7554/elife.60969
复制
发表时间：
2021-02-03
期刊：
影响因子：
7.7
通讯作者：
Shiozaki K
中科院分区：
文献类型：
--
作者：
Fukuda T;Sofyantoro F;Tai YT;Chia KH;Matsuda T;Murase T;Morozumi Y;Tatebe H;Kanki T;Shiozaki K
雷帕霉素复合物1（TORC 1）的哺乳动物靶点由GATOR 1亚复合物及其抑制剂GATOR 2亚复合物组成的GATOR复合物控制，对氨基酸饥饿敏感。以前，我们确定了裂变酵母GATOR 1，防止TORC 1的失调激活。在这里，我们报告的GATOR 2在裂殖酵母的鉴定和表征。出乎意料的是，GATOR 2亚基Sea 3，哺乳动物WDR 59的直系同源物，在物理和功能上接近GATOR 1，而不是GATOR 2，从而减弱TORC 1活性。裂变酵母GATOR复合物响应于氨基酸饥饿而被抑制TORC 1调节，这反而激活Gcn 2途径以抑制TORC 1并诱导自噬。另一方面，氮饥饿通过GATOR 1-Sea 3复合物、Gcn 2途径和TSC复合物（另一种保守的TORC 1抑制剂）的联合作用抑制TORC 1。因此，多个平行的信号传导途径实现TORC 1的负调控以确保适当的细胞饥饿反应。
Mammalian target of rapamycin complex 1 (TORC1) is controlled by the GATOR complex composed of the GATOR1 subcomplex and its inhibitor, the GATOR2 subcomplex, sensitive to amino acid starvation. Previously, we identified fission yeast GATOR1 that prevents deregulated activation of TORC1. Here, we report identification and characterization of GATOR2 in fission yeast. Unexpectedly, the GATOR2 subunit Sea3, an ortholog of mammalian WDR59, is physically and functionally proximal to GATOR1, rather than GATOR2, attenuating TORC1 activity. The fission yeast GATOR complex is dispensable for TORC1 regulation in response to amino acid starvation, which instead activates the Gcn2 pathway to inhibit TORC1 and induce autophagy. On the other hand, nitrogen starvation suppresses TORC1 through the combined actions of the GATOR1-Sea3 complex, the Gcn2 pathway, and the TSC complex, another conserved TORC1 inhibitor. Thus, multiple, parallel signaling pathways implement negative regulation of TORC1 to ensure proper cellular starvation responses.