2. Academic Validation
  3. CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity

CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity

  • Mol Cell. 2026 Jan 22;86(2):362-375.e4. doi: 10.1016/j.molcel.2025.12.016.
Chan Liu 1,  Yifan Zhang 2,  Yilun Wang 1,  Min Wu 1,  Yunchao Li 1,  Jiashuai Wei 1,  Jiawen Shi 1,  Rong Wang 2,  Li Su 3,  Tingting Yang 4,  Jin Li 4,  Junjie Xiao 4,  Jianping Ding 5,  Tianlong Zhang 6
Affiliations

Affiliations

  • 1 Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University, The Sixth People's Hospital of Nantong, Shanghai Engineering Research Center of Organ Repair, Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), School of Medicine, Shanghai University, Nantong 226011, China.
  • 2 Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • 3 Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
  • 4 School of Life Science, Shanghai University, Shanghai 200444, China.
  • 5 Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, 393 Hua-Xia Zhong Road, Shanghai 201210, China. Electronic address: [email protected].
  • 6 Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University, The Sixth People's Hospital of Nantong, Shanghai Engineering Research Center of Organ Repair, Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), School of Medicine, Shanghai University, Nantong 226011, China. Electronic address: [email protected].
PMID: 41506264 DOI: 10.1016/j.molcel.2025.12.016
Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, responding to amino acid availability. While mTORC1 is modulated by amino acid sensors like CASTOR1, the mechanisms driving its dynamic response to fluctuating amino acid levels remain unclear. Here, we investigate the role of CASTOR2, an understudied CASTOR1 homolog, in regulating mTORC1 activity. We show that CASTOR1 and CASTOR2 bind to arginine similarly but differ in their sensitivity: CASTOR1 responds to low arginine levels, whereas CASTOR2 responds to high arginine concentrations. Both proteins interact with the GATOR2 component Mios, inhibiting its binding to GATOR1. Arginine binding to CASTOR1/2 induces conformational changes at the aspartate kinase, chorismate mutase, and TyrA (ACT) domain (ACT2-ACT4) interface, leading to its dissociation from Mios. Functionally, we demonstrate that CASTOR proteins are highly expressed in muscle tissue and, in C2C12 cells, they regulate mTORC1 and myogenesis in response to different arginine availability. These findings highlight how CASTOR proteins function as dual arginine sensors to fine-tune mTORC1 activity.

Keywords

CASTOR1; CASTOR2; GATOR1; GATOR2; amino acid sensor; arginine; mTORC1 signaling; myogenesis.

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