TRAF4‐Mediated LAMTOR1 Ubiquitination Promotes mTORC1 Activation and Inhibits the Inflammation‐Induced Colorectal Cancer Progression

Mechanistic target of rapamycin complex 1 (mTORC1) is a conserved serine/threonine kinase that integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activation requires tethering to lysosomes by the Ragulator‐Rag complex. However, the dynamic regulation of the inter...

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Published in:Advanced science 2024-03, Vol.11 (12), p.e2301164-n/a
Main Authors: Zhao, Linlin, Gao, Ni, Peng, Xiaoping, Chen, Lei, Meng, Tong, Jiang, Cong, Jin, Jiali, Zhang, Jiawen, Duan, Qiuhui, Tian, Hongling, Weng, Linjun, Wang, Xinbo, Tan, Xiao, Li, Yaxu, Qin, Huanlong, Yuan, Jian, Ge, Xin, Deng, Lu, Wang, Ping
Format: Article
Language:English
Subjects:
Amino acids
Autophagy
Colorectal cancer
Kinases
LAMTOR1
Localization
mTORC1
Mutation
Plasmids
Proteins
Rag GTPase
TRAF4
ubiquitination
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Summary:Mechanistic target of rapamycin complex 1 (mTORC1) is a conserved serine/threonine kinase that integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activation requires tethering to lysosomes by the Ragulator‐Rag complex. However, the dynamic regulation of the interaction between Ragulator and Rag guanosine triphosphatase (GTPase) remains unclear. In this study, that LAMTOR1, an essential component of Ragulator, is dynamically ubiquitinated depending on amino acid abundance is reported. It is found that the E3 ligase TRAF4 directly interacts with LAMTOR1 and catalyzes the K63‐linked polyubiquitination of LAMTOR1 at K151. Ubiquitination of LAMTOR1 by TRAF4 promoted its binding to Rag GTPases and enhanced mTORC1 activation, K151R knock‐in or TRAF4 knock‐out blocks amino acid‐induced mTORC1 activation and accelerates the development of inflammation‐induced colon cancer. This study revealed that TRAF4‐mediated LAMTOR1 ubiquitination is a regulatory mechanism for mTORC1 activation and provides a therapeutic target for diseases involving mTORC1 dysregulation. A model demonstrating the ubiquitination of LAMTOR1 in response to amino acids availability. Upon amino acids stimulation, the E3 ligase TRAF4 bind to LAMTOR1 and promote the K63‐linked ubiquitination of LAMTOR1 at K151, which increased its binding with Rag GTPases and the activation of mTORC1.
ISSN:2198-3844
2198-3844
DOI:10.1002/advs.202301164