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An arginine sensor for mTORC1

Binding of arginine to CASTOR1 disrupts its binding to a complex that promotes mTORC1 activity. Amino acid stimulation triggers the lysosomal translocation of mammalian target of rapamycin complex 1 (mTORC1), a multiprotein complex that couples nutrient availability to cell growth–promoting pathways. Chantranupong et al. identified CASTOR1 as an arginine sensor for mTORC1 (see also Hughes Hallett and Manning). A protein-protein interaction database indicated that CASTOR1 and CASTOR2 (which shares 63% identity with CASTOR1) interacted with various components of GATOR2, a protein complex that promotes mTORC1 activity. Both CASTOR1 and CASTOR2 contain two ACT domains—which bind to various small molecules, including amino acids—and CASTOR1 and CASTOR2 formed homodimers and heterodimers. Overexpressed CASTOR1 and CASTOR2 coimmunoprecipitated with endogenous mios (a component of GATOR2), as well as with mios overexpressed by itself or in combination with other GATOR2 components. The interaction of GATOR2 with CASTOR1, but not with CASTOR2, was strengthened in cells subjected to amino acid deprivation and abolished upon amino acid replenishment. In particular, arginine deprivation decreased the interaction of mios with CASTOR1 homodimers or CASTOR1-CASTOR2 heterodimers in a dose-dependent fashion. When expressed as separate fragments, the CASTOR2 ACT domains constitutively bound to each other, whereas the interaction of the CASTOR1 ACT domains required arginine. These results suggested that arginine bound to CASTOR1 but not CASTOR2. In vitro assays indicated that arginine bound to the CASTOR1 homodimer and the CASTOR1-CASTOR2 heterodimer with a Kd of approximately 30 μM. Knockdown of CASTOR1 prevented arginine depletion from affecting mTORC1 activation. mTORC1 activation was suppressed by overexpression of CASTOR2 independently of arginine availability, suggesting that CASTOR2 constitutively inhibits mTORC1 activity. A CASTOR1 mutant that could not bind to arginine showed increased association with GATOR2 regardless of whether arginine was added or not, and in CASTOR1 knockdown cells reconstituted with this mutant, arginine failed to stimulate mTORC1 activity. Thus, CASTOR1 and CASTOR2 are inhibitors of mTORC1, and binding of arginine to CASTOR1 enables GATOR2 to enhance mTORC1 activity. L. Chantranupong, S. M. Scaria, R. A. Saxton, M. P. Gygi, K. Shen, G. A. Wyant, T. Wang, J. W. Harper, S. P. Gygi, D. M. Sabatini, The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153–164 (2016). [PubMed] J. E. Hughes Hallett, B. D. Manning , CASTORing new light on amino acid sensing. Cell 165, 15–17 (2016). [PubMed]