MTORC1, as a sensor of nutrition signal in microenvironment, can sense amino acid, growth factor, glucose, cholesterol and other signals in microenvironment, and then regulate several key processes in cell and organism, such as glucose metabolism, protein metabolism, lipid metabolism, cell autophagy and so on [1, 2]. However, when the key proteins of mTORC1 signaling pathway (mTOR, GATOR, PTEN, TSC, LKB, AMPK, etc.) mutate, it will lead to the disorder of mTORC1 activity, and then lead to the disorder of cell metabolism and cell proliferation, which will also be the main inducement of many metabolic related diseases [3, 4]. It can be seen that mTORC1 signaling pathway is the core of maintaining the metabolic balance of the body, and also an important frontier field of cell metabolism. Further exploration of the regulatory mechanism of mTORC1 signaling pathway can provide important theories for molecular diagnosis, accurate classification, prognosis analysis and targeted therapy based on metabolic diseases in clinic.

The activation of mTORC1 is mainly due to the synergistic action of amino acid and growth factor signal, in which amino acid signal mainly regulates the localization of mTORC1 on lysosomes through Rags complex, while growth factor signal mainly promotes the activity of mTORC1 by activating Rheb [2,5].

Prof. Wang Ping’s research group has been focusing on the interaction mechanism between tumor cells and microenvironment, a key scientific question in tumor biology for a long time, and discusses ubiquitination regulation of tumor microenvironment systematically. A large number of evidences have shown that ubiquitination plays an important role in tumorigenesis. As an important post-translational modification of proteins, ubiquitination (including sumoylation) has always been the focus and hotspot of tumor biology research. Ubiquitination is a reversible enzyme cascade reaction, which is precisely regulated by ubiquitin ligases and depubiquitinases. So far, nearly 600 E3 ubiquitin ligases and 100 depubiquitinases have been reported[6-8]. However, the relationship between the most E3 ubiquitin ligases and depubiquitinases and tumorigenesis is not clear yet.

So, around the scientific question of "whether ubiquitination participates in the nutrition signal in mTORC1 sensing microenvironment", Wang Ping group of Tongji University School of Medicine and Hui Kuanlin group of MD Anderson Cancer Center published papers "back to back" in 2015, and found that ubiquitination could participate in the amino acid signal in mTORC1 sensing microenvironment through RagA [9, 10]. In 2017, Professor Wei Wenyi from Harvard Medical School found that ubiquitination could participate in the synergistic regulation of mTORC1 and mTORC2 signaling pathways through GβL [11]. In addition, in 2018, Liu Ying research group of Institute of molecular medicine of Peking University / Peking University and Tsinghua University Joint Center for life sciences, found that ubiquitination participated in the amino acid signal of mTORC1 sensing microenvironment through the degradation of DEPDC5 (Nature: Liu Ying group made important progress in mTORC1, tumorigenesis and senescence regulation - Comments from Professor Liu Wei) [12].

Recently, Wang Ping's research group published a research paper entitled Ubiquitination of Rheb governs growth factor-induced mTORC1 activation in Cell Research. This paper expounded that ubiquitination could participate in mTORC1 sensing growth factor signal in microenvironment through Rheb.

Rheb, as a direct activator of mTORC1, plays a key role in the activation of mTORC1 [13]. This study found that Rheb not only could be modified by ubiquitination, but also its ubiquitination was regulated by growth factor signal, its E3 ubiquitin ligase RNF152, its depubiquitinase USP4 and its ubiquitin site K8 were identified by screening (as shown in the figure below).

As a post-translational modification, ubiquitination could regulate the stability, activity or localization of the substrate. This study found that ubiquitination of Rheb would not affect the stability of Rheb protein. By detecting the activity of RNF152 and USP4 in MEF, it was found that ubiquitination could inhibit the activity of small G protease of Rheb. Further study showed that ubiquitination could inhibit the small G protease activity of Rheb by promoting the integration of Rheb and TSC2.

At the same time, through the MEF cells of RNF152, USP4 and K8R knockin cell lines, it was found that ubiquitination of Rheb could regulate the activity, cell proliferation, cell size and autophagy of mTORC1. In addition, the study also found that ubiquitination of Rheb played an important role in the occurrence and development of tumors through subcutaneous tumorigenesis in nude mice and AOM-DSS-induced colorectal cancer model.

In conclusion, this work revealed that ubiquitination could participate in the growth factor signal in mTORC1 sensing microenvironment through Rheb, and expounded that ubiquitination of Rheb was an important regulatory mechanism for the occurrence and development of tumors(as shown in the figure below).

It was reported that Deng Lu and Chen Lei from Prof. Wang Ping's research group were the co-first authors of this paper, and Prof. Wang Ping was the corresponding author.

Reference:

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