小柯机器人

意大利Telethon遗传与医学研究所（TIGEM）Andrea Ballabio研究组取得最新进展。他们发现底物特异的雷帕霉素复合物1（mTORC1）途径是Birt-Hogg-Dubé综合征的基础。相关论文发表在2020年7月1日出版的《自然》杂志上。

他们显示了转录因子EB（TFEB），溶酶体生物发生和自噬的主要调节子，是通过Rag GTPases介导的底物特异性机制被mTORC1磷酸化的。由于这种机制，TFEB的磷酸化（不同于mTORC1的其他底物，如S6K和4E-BP1）严格依赖于氨基酸介导的RagC和RagD GTPases的活化，但对由生长因子诱导的RHEB活性不敏感。这种机制在Birt-Hogg-Dubé综合征中起着至关重要的作用，这种疾病是由RagC和RagD激活剂卵泡蛋白（FLCN）突变引起的，其特征是皮肤良性肿瘤、肺和肾囊肿以及肾细胞癌。

他们发现，在Birt–Hogg–Dubé综合征小鼠模型中，TFEB的组成型激活是肾脏异常和mTORC1过度活跃的主要驱动力。因此，这些小鼠肾脏中TFEB的敲除可完全挽救疾病的表型和相关的致死率，并使mTORC1活性正常化。他们的发现确定了一种机制，该机制可实现mTORC1底物的差异磷酸化，其失调可导致肾囊肿和癌症。

据了解，mTORC1的机制目标是关键的代谢枢纽，通过在多种底物上发挥激酶活性来控制细胞对环境因素的反应。然而，人们尚不清楚mTORC1是否通过差异化特定底物的磷酸化来响应多种刺激。

附：英文原文

Title: A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome

Author: Gennaro Napolitano, Chiara Di Malta, Alessandra Esposito, Mariana E. G. de Araujo, Salvatore Pece, Giovanni Bertalot, Maria Matarese, Valerio Benedetti, Angela Zampelli, Taras Stasyk, Diletta Siciliano, Alessandro Venuta, Marcella Cesana, Claudia Vilardo, Edoardo Nusco, Jlenia Monfregola, Alessia Calcagn, Pier Paolo Di Fiore, Lukas A. Huber, Andrea Ballabio

Issue&Volume: 2020-07-01

Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates1,2,3. However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy4,5, is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases. Owing to this mechanism, the phosphorylation of TFEB—unlike other substrates of mTORC1, such as S6K and 4E-BP1— is strictly dependent on the amino-acid-mediated activation of RagC and RagD GTPases, but is insensitive to RHEB activity induced by growth factors. This mechanism has a crucial role in Birt–Hogg–Dubé syndrome, a disorder that is caused by mutations in the RagC and RagD activator folliculin (FLCN) and is characterized by benign skin tumours, lung and kidney cysts and renal cell carcinoma6,7. We found that constitutive activation of TFEB is the main driver of the kidney abnormalities and mTORC1 hyperactivity in a mouse model of Birt–Hogg–Dubé syndrome. Accordingly, depletion of TFEB in kidneys of these mice fully rescued the disease phenotype and associated lethality, and normalized mTORC1 activity. Our findings identify a mechanism that enables differential phosphorylation of mTORC1 substrates, the dysregulation of which leads to kidney cysts and cancer.

DOI: 10.1038/s41586-020-2444-0

Source: https://www.nature.com/articles/s41586-020-2444-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html