【原】C2 Assembly Regulated by USP9X-Mediated RICTOR Deubiquitination

mTORC2 Assembly Is Regulated by USP9X-Mediated Deubiquitination of RICTOR

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|核心内容：

雷帕霉素复合物2(mTORC2)的机械作用靶点控制细胞对环境输入的代谢和存活。

mTORC2信号的失调与多种人类疾病有关，包括癌症和代谢紊乱，这突出了严格控制 mTORC2的重要性。

虽然mTORC2的组装是其活性的一个关键决定因素，但是调节这一事件的因素并没有得到很好的理解，而且不清楚这一过程是否受生长因子的调节。

在这里，我们提供了来自人类细胞系和小鼠的数据，描述了生长因子调节泛素特异性蛋白酶9X (USP9X)去泛素化酶刺激 mTORC2组装和活性的机制。

USP9X 去除 RICTOR 中 lys63连接的泛素，促进其与 mTOR 的相互作用，从而促进 mTORC2信号转导。

由于 mTORC2是细胞内稳态的中心，了解调节 mTORC2朝向其下游靶点激活的机制对于我们理解生理过程和开发新的病理学治疗策略至关重要。

GF~USP9X~mTORC2(~less mTORC1?)

原文摘要：

The mechanistic target of rapamycin complex 2 (mTORC2) controls cell metabolism and survival in response to environmental inputs. 

Dysregulation of mTORC2 signaling has been linked to diverse human diseases, including cancer and metabolic disorders, highlighting the importance of a tightly controlled mTORC2. 

While mTORC2 assembly is a critical determinant of its activity, the factors regulating this event are not well understood, and it is unclear whether this process is regulated by growth factors. 

Here, we present data, from human cell lines and mice, describing a mechanism by which growth factors regulate ubiquitin-specific protease 9X (USP9X) deubiquitinase to stimulate mTORC2 assembly and activity. 

USP9X removes Lys63-linked ubiquitin from RICTOR to promote its interaction with mTOR, thereby facilitating mTORC2 signaling. 

As mTORC2 is central for cellular homeostasis, understanding the mechanisms regulating mTORC2 activation toward its downstream targets is vital for our understanding of physiological processes and for developing new therapeutic strategies in pathology.

Highlights

• USP9X depletion decreases mTORC2 signaling through RICTOR

• RICTOR ubiquitination regulates the RICTOR-mTOR interaction

• Growth factors regulate USP9X expression to regulate hepatic mTORC2 signaling

hepatic

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参考文献：https://www./cell-reports/fulltext/S2211-1247(20)31553-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124720315539%3Fshowall%3Dtrue

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