ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C.,Nature Cell Biology

当前位置： X-MOL 学术 › Nat. Cell Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2019-09-23 , DOI: 10.1038/s41556-019-0391-5
Chun-Yan Lim _{1,

2} , Oliver B Davis _{1,

2} , Hijai R Shin _{1,

2} , Justin Zhang _{1,

2} , Charles A Berdan _{1,

3} , Xuntian Jiang ₄ , Jessica L Counihan _{1,

3} , Daniel S Ory ₄ , Daniel K Nomura _{1,

3} , Roberto Zoncu _{1,

2}

Affiliation

Cholesterol activates the master growth regulator, mTORC1 kinase, by promoting its recruitment to the surface of lysosomes by the Rag guanosine triphosphatases (GTPases). The mechanisms that regulate lysosomal cholesterol content to enable mTORC1 signalling are unknown. Here, we show that oxysterol binding protein (OSBP) and its anchors at the endoplasmic reticulum (ER), VAPA and VAPB, deliver cholesterol across ER-lysosome contacts to activate mTORC1. In cells lacking OSBP, but not other VAP-interacting cholesterol carriers, the recruitment of mTORC1 by the Rag GTPases is inhibited owing to impaired transport of cholesterol to lysosomes. By contrast, OSBP-mediated cholesterol trafficking drives constitutive mTORC1 activation in a disease model caused by the loss of the lysosomal cholesterol transporter, Niemann-Pick C1 (NPC1). Chemical and genetic inactivation of OSBP suppresses aberrant mTORC1 signalling and restores autophagic function in cellular models of Niemann-Pick type C (NPC). Thus, ER-lysosome contacts are signalling hubs that enable cholesterol sensing by mTORC1, and targeting the sterol-transfer activity of these signalling hubs could be beneficial in patients with NPC.

中文翻译：

ER-溶酶体接触使 mTORC1 能够感应胆固醇并驱动 Niemann-Pick C 型中的异常生长信号。

胆固醇通过 Rag 鸟苷三磷酸酶 (GTPases) 促进其募集到溶酶体表面，从而激活主要的生长调节剂 mTORC1 激酶。调节溶酶体胆固醇含量以启用 mTORC1 信号传导的机制尚不清楚。在这里，我们展示了氧甾醇结合蛋白 (OSBP) 及其在内质网 (ER)、VAPA 和 VAPB 的锚点，通过 ER-溶酶体接触传递胆固醇以激活 mTORC1。在缺乏 OSBP 但没有其他与 VAP 相互作用的胆固醇载体的细胞中，由于胆固醇向溶酶体的转运受损，Rag GTP 酶对 mTORC1 的募集受到抑制。相比之下，在由溶酶体胆固醇转运蛋白 Niemann-Pick C1 (NPC1) 缺失引起的疾病模型中，OSBP 介导的胆固醇转运驱动组成型 mTORC1 激活。OSBP 的化学和遗传失活抑制异常 mTORC1 信号传导并恢复 Niemann-Pick C 型 (NPC) 细胞模型中的自噬功能。因此，ER-溶酶体接触是能够通过 mTORC1 感知胆固醇的信号中枢，靶向这些信号中枢的甾醇转移活性可能对 NPC 患者有益。

更新日期：2019-09-23

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南