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TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling

机译：TRAF2和OTUD7B控制泛素依赖性开关，该开关调节mTORC2信号传导

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摘要

The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways(1). mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORC1) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer(1). Thus, both mTORC1 and mTORC2 kinase activity is tightly controlled in cells. mTORC1 is activated by both nutrients(3-6) and growth factors(7), whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling(8-10). Although both mTOR and G beta L (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11-15), it remains largely unclear what drives the dynamic assembly of these two functionally distinct complexes. Here we show, in humans and mice, that the K63-linked polyubiquitination status of G beta L dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of G beta L, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12-14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from G beta L to promote G beta L interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in G beta L, by either K305R/K313R mutations or a melanoma-associated G beta L(Delta W297) truncation, leads to elevated mTORC2 formation, which facilitates tumorigenesis, in part by activating AKT oncogenic signalling. In support of a physiologically pivotal role for OTUD7B in the activation of mTORC2/AKT signalling, genetic deletion of Otud7b in mice suppresses Akt activation and Kras-driven lung tumorigenesis in vivo. Collectively, our study reveals a G beta L-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions.
机译：雷帕霉素（mTOR）的机制靶标在各种生理刺激的整合中起着关键作用，以调节几种细胞的生长和代谢途径（1）。 mTOR主要在两个结构相关但功能不同的多组分激酶复合物mTOR复合物1（mTORC1）和mTORC2（参考文献1、2）中起催化亚基的作用。 mTOR信号的失调与多种人类疾病有关，包括代谢紊乱和癌症（1）。因此，mTORC1和mTORC2激酶活性均在细胞中受到严格控制。营养物质（3-6）和生长因子（7）均激活了mTORC1，而mTORC2主要对细胞外信号做出反应，例如生长因子触发的PI3K信号传导激活（8-10）。尽管mTOR和G beta L（也称为MLST8）都组装成mTORC1和mTORC2（参考文献11-15），但仍不清楚是什么因素驱动了这两个功能不同的复合物的动态组装。在这里，我们证明了在人和小鼠中，GβL的K63连接的多聚泛素状态决定了mTORC2形成和激活的稳态。从机理上讲，TRAF2 E3泛素连接酶促进K63连接的GβL的多聚泛素化，从而破坏其与独特的mTORC2组分SIN1（参考文献12-14）的相互作用，从而促进mTORC1的形成。相比之下，OTUD7B去泛素酶从GβL去除聚泛素链以促进GβL与SIN1的相互作用，从而促进mTORC2响应各种生长信号而形成。此外，由于K305R / K313R突变或黑色素瘤相关的GβL（Delta W297）截短而导致GβL中关键泛素化残基的丢失，导致mTORC2形成增加，这部分通过激活AKT致癌信号而促进肿瘤发生。为了支持OTUD7B在mTORC2 / AKT信号激活中的生理关键作用，在小鼠中Otud7b的基因缺失在体内抑制Akt激活和Kras驱动的肺肿瘤发生。总的来说，我们的研究揭示了一个GβL泛素化依赖性开关，可在生理和病理条件下微调mTORC2激酶的动态组织和激活。

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  • 来源
    《Nature》 |2017年第7654期|365-369|共5页
  • 作者

    Wang Bin; Jie Zuliang; Joo Donghyun; Ordureau Alban; Liu Pengda; Gan Wenjian; Guo Jianping; Zhang Jinfang; North Brian J.; Dai Xiangpeng; Cheng Xuhong; Bian Xiuwu; Zhang Lingqiang; Harper J. Wade; Sun Shao-Cong; Wei Wenyi;

  • 作者单位

    Third Mil Med Univ, Daping Hosp, Inst Surg Res, Dept Gastroenterol, Chongqing 400042, Peoples R China;

    Univ Texas MD Anderson Canc Ctr, Dept Immunol, 7455 Fannin St,Box 902, Houston, TX 77030 USA;

    Univ Texas MD Anderson Canc Ctr, Dept Immunol, 7455 Fannin St,Box 902, Houston, TX 77030 USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA;

    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA;

    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA;

    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA;

    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA;

    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA;

    Univ Texas MD Anderson Canc Ctr, Dept Immunol, 7455 Fannin St,Box 902, Houston, TX 77030 USA;

    Third Mil Med Univ, Southwest Hosp, Minist Educ China, Inst Pathol, Chongqing 400038, Peoples R China;

    Beijing Inst Radiat Med, Collaborat Innovat Ctr Canc Med, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing 100850, Peoples R China;

    Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA;

    Univ Texas MD Anderson Canc Ctr, Dept Immunol, 7455 Fannin St,Box 902, Houston, TX 77030 USA;

    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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