State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.
Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Nature. 2018 May;557(7706):585-589. doi: 10.1038/s41586-018-0128-9. Epub 2018 May 16.
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental cues, including amino acids. Deregulation of mTORC1 has been linked with metabolic diseases, cancer and ageing. In response to amino acids, mTORC1 is recruited by the Rag GTPases to the lysosome, its site of activation. The GATOR1 complex, consisting of DEPDC5, NPRL3 and NPRL2, displays GAP activity to inactivate Rag GTPases under amino-acid-deficient conditions . However, it is unclear how the inhibitory function of GATOR1 is released upon amino acid stimulation. Here we find that in response to amino acids, the CUL3-KLHL22 E3 ubiquitin ligase promotes K48-linked polyubiquitination and degradation of DEPDC5, an essential subunit of GATOR1. KLHL22 plays a conserved role to mediate the activation of mTORC1 and downstream events in mammals and nematodes. Depletion of MEL-26, the Caenorhabditis elegans orthologue of KLHL22, extends worm lifespan. Moreover, KLHL22 levels are elevated in tumours of breast cancer patients, whereas DEPDC5 levels are correspondingly reduced. Depletion of KLHL22 in breast cancer cells suppresses tumour growth in nude mice. Therefore, pharmacological interventions targeting KLHL22 may have therapeutic potential for the treatment of breast cancer and age-related diseases.
雷帕霉素哺乳动物靶标（mTOR）复合物 1（mTORC1）是细胞生长的主要调节因子，对包括氨基酸在内的多种环境线索作出反应。mTORC1 的失调与代谢疾病、癌症和衰老有关。在氨基酸的作用下，mTORC1 被 Rag GTPases 募集到溶酶体，溶酶体是其激活的部位。由 DEPDC5、NPRL3 和 NPRL2 组成的 GATOR1 复合物在氨基酸缺乏的条件下表现出 GAP 活性，使 Rag GTPases 失活。然而，目前尚不清楚 GATOR1 的抑制功能在氨基酸刺激下是如何释放的。在这里，我们发现，在氨基酸的作用下，CUL3-KLHL22 E3 泛素连接酶促进 GATOR1 的必需亚基 DEPDC5 的 K48 连接多泛素化和降解。KLHL22 在哺乳动物和线虫中发挥保守作用，介导 mTORC1 的激活和下游事件。C. elegans 中 KLHL22 的同源物 MEL-26 的缺失延长了线虫的寿命。此外，乳腺癌患者肿瘤中的 KLHL22 水平升高，而 DEPDC5 水平相应降低。在乳腺癌细胞中耗尽 KLHL22 会抑制裸鼠肿瘤的生长。因此，针对 KLHL22 的药理学干预可能具有治疗乳腺癌和与年龄相关疾病的治疗潜力。
