Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity.

ABSTRACT

The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.

Cells need to be able to sense and respond to signals from their environment. A group (or complex) of conserved proteins called mTORC1 acts a key signaling hub that regulates cell growth and many other processes. This complex can be activated by many different signals from outside the cell. However, mTORC1 can only be activated by these signals if there is also a good supply of amino acids ­ which are needed to make new proteins ­ within the cell. The amino acids are thought to be presented to mTORC1 on the outer surface of cellular compartments known as lysosomes. A protein called Rheb on the surface of the lysosomes activates mTORC1, while a protein complex called TSC inhibits the activity of Rheb to regulate mTORC1 activity. Previous studies have shown that some amino acids influence whether mTORC1 can be activated by affecting whether it is localized to the lysosomes or not. Here, Carroll et al. explored how an amino acid called arginine regulates mTORC1. The experiments show that arginine is the major amino acid that influences whether mTORC1 can be activated in several different types of human cell. When cells were deprived of arginine, the activity of the complex was strongly suppressed. However, microscopy showed that arginine had no effect on whether mTORC1 was found at the lysosomes or not, which suggests that arginine might be acting in a different way to other amino acids. Further experiments found that a lack of arginine led to an increase in the number of TSC complexes at the lysosomes. This led to the inhibition of Rheb and therefore prevented mTORC1 from being activated. Together, Carroll et al.'s findings provide evidence that the different signals that regulate mTORC1 signaling cooperate to a greater extent than previously thought. A future challenge will be to understand the molecular details of how the arginine is detected.