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一个基质特定的mTORC1通路是Birt-Hogg-Dubé综合征的基础

Gennaro Napolitano^1,2, Chiara Di Malta¹, Alessandra Esposito¹

¹Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.

|July 3, 2020

概括

通过Rag GTPase依赖的途径化转录因子EB (TFEB),揭示了mTORC1信号传递中的基质特异性的机制. 这一途径对于Birt-Hogg-Dubé综合征至关重要.

科学领域:

细胞生物学
分子生物学
生物化学

背景情况:

拉巴胺复合体1 (mTORC1) 的机械标是细胞代谢和生长的中心调节剂.
了解mTORC1如何在对各种刺激的反应中对其基质进行化,对于理解细胞信号通路至关重要.

研究的目的:

研究mTORC1酸化的基质特异性.
阐明Rag GTPases在调解mTORC1基质选择中的作用.
探索这种机制在Birt-Hogg-Dubé综合征中的含义.

主要方法:

使用生物化学试验研究了mTORC1基质酸化.
使用Rag GTPases和RHEB的基因操纵.
分析了一种Birt-Hogg-Dubé综合征的小鼠模型.

主要成果:

通过Rag GTPase依赖机制通过mTORC1酸化的基质确定转录因子EB (TFEB).
证明mTORC1的TFEB化与其他基质如S6K和4E-BP1不同,依赖RagC/D,但对RHEB不敏感.
在Birt-Hogg-Dubé综合征小鼠模型中显示构成TFEB激活驱动脏异常和mTORC1过活.
发现受影响脏的TFEB枯竭挽救了疾病表型,并使mtORC1活动正常化.

结论:

发现了一种由Rag GTPases介导的mTORC1基质特异性的新机制,特别是针对TFEB.
这种TFEB酸化途径的失调与Birt-Hogg-Dubé综合征的发生有关,包括囊和癌症.
针对TFEB可能为Birt-Hogg-Dubé综合征提供治疗潜力.

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