GATOR2 regulates the nutrient-dependent recruitment of GATOR1 to lysosomes

Abstract

TORC1 is a central regulator of cellular metabolism. TORC1 activation depends on its recruitment to the lysosome, a process mediated by the Rag GTPases and their upstream regulator, the GATOR complex. GATOR consists of two subcomplexes: GATOR1, which converts the Rag GTPases into an inactive form during nutrient starvation by acting as a GAP towards RagA, and GATOR2, which counteracts GATOR1 through an unknown mechanism. Here we dissect the GATOR-Rag GTPases network at the cellular and subcellular level in Drosophila using genomically tagged proteins. We find that GATOR2 maintains GATOR1 in the GAP-inactive state under nutrient-replete conditions. Moreover, using fluorescent recovery after photobleaching we show that while GATOR1 and GATOR2 are recruited to lysosomes as a supercomplex in fed conditions, their recruitment becomes decoupled during starvation. Taken together, our findings support a model in which GATOR1 forms an inactive supercomplex with GATOR2 under nutrient-rich conditions. However, upon nutrient starvation, this supercomplex dissociates, enabling GATOR1 to adopt a GAP-active state and inhibit the Rag GTPases, thereby preventing the recruitment and activation of TORC1 on lysosomes. Finally, our data identify Wdr59 as a critical regulator of this nutrient-dependent remodeling that is required to relieve GATOR2-mediated inhibition of GATOR1.