Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling
Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling
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DOI：
10.1074/jbc.m115.691584
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发表时间：
2016-03-04
影响因子：
4.8
通讯作者：
Hedstrom, Lizbeth
中科院分区：
文献类型：
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作者：
Coffey, Rory T.;Shi, Yuntao;Hedstrom, Lizbeth
哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）是细胞代谢、生长和增殖的主要调节因子。mTORC 1与许多疾病有关，如癌症、糖尿病和神经变性，并且是延长寿命的靶点。在这里，我们报告了mTORC 1信号的小分子抑制剂（Cbz-B3 A）。Cbz-B3 A抑制eIF 4 E结合蛋白1（4 EBP 1）的磷酸化并阻断68%的翻译。相比之下，雷帕霉素优先抑制p70（S6 k）的磷酸化并阻断35%的翻译。Cbz-B3 A似乎不直接与mTORC 1结合，而是与泛素1、2和4结合。泛素2的敲除，而不是泛素1和4，降低了4 EBP 1的磷酸化，表明泛素2激活mTORC 1。泛素2和4的敲低降低了Cbz-B3 A对4 EBP 1磷酸化的作用。Cbz-B3 A减缓一些人白血病细胞系的细胞生长，但没有细胞毒性。因此，Cbz-B3 A证实了一种抑制mTORC 1信号传导的新策略，可用于治疗许多人类疾病。我们建议，Cbz-B3 A揭示了一个以前不受重视的调节途径协调胞质蛋白质的质量控制和mTORC 1信号。
Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular metabolism, growth, and proliferation. mTORC1 has been implicated in many diseases such as cancer, diabetes, and neurodegeneration, and is a target to prolong lifespan. Here we report a small molecule inhibitor (Cbz-B3A) of mTORC1 signaling. Cbz-B3A inhibits the phosphorylation of eIF4E-binding protein 1 (4EBP1) and blocks 68% of translation. In contrast, rapamycin preferentially inhibits the phosphorylation of p70(S6k) and blocks 35% of translation. Cbz-B3A does not appear to bind directly to mTORC1, but instead binds to ubiquilins 1, 2, and 4. Knockdown of ubiquilin 2, but not ubiquilins 1 and 4, decreases the phosphorylation of 4EBP1, suggesting that ubiquilin 2 activates mTORC1. The knockdown of ubiquilins 2 and 4 decreases the effect of Cbz-B3A on 4EBP1 phosphorylation. Cbz-B3A slows cellular growth of some human leukemia cell lines, but is not cytotoxic. Thus Cbz-B3A exemplifies a novel strategy to inhibit mTORC1 signaling that might be exploited for treating many human diseases. We propose that Cbz-B3A reveals a previously unappreciated regulatory pathway coordinating cytosolic protein quality control and mTORC1 signaling.