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

Jan 8, 2026Molecular cell

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

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Abstract

CASTOR1 and CASTOR2 bind to arginine, with CASTOR1 responding to low levels and CASTOR2 to high concentrations.

CASTOR1 and CASTOR2 are involved in regulating mTORC1 activity in response to arginine availability.
Both CASTOR proteins interact with Mios, a component of the GATOR2 complex, influencing mTORC1 signaling.
Binding of arginine to CASTOR proteins causes changes in their structure that affect their interaction with Mios.
CASTOR proteins are predominantly expressed in muscle tissue and play a role in muscle cell development based on arginine levels.
These findings suggest that CASTOR proteins may act as dual sensors for arginine to modulate mTORC1 activity.

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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.

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

Abstract

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