eIF4A moonlights as an off switch for TORC1.

T arget of rapamycin complex 1 (TORC1) is an evolutionarily conserved regulator of cell growth and metabolism. It integrates multiple inputs (hormones, growth factors, amino acids, and cellular energy) to activate anabolic processes such as protein, lipid, and nucleotide synthesis, and to inhibit catabolic processes including autophagy. Inputs impinge on TORC1 via the TSC complex (composed of tuberous sclerosis complex 1 (TSC1), TSC2, and TBC1D7). The tumor-suppressing TSC complex is a GTPase-activating protein (GAP) for the small GTPase Rheb, a direct activator of TORC1, and thereby an upstream TORC1 inhibitor (Shimobayashi & Hall, 2014). TORC1 regulation in response to amino acids ensures that translation is coupled to the availability of building blocks. The conserved Rag GTPases are key components of the amino acid-sensing branch upstream of TORC1. When amino acids are present, the Rag GTPases adopt an active conformation to recruit TORC1 to the lysosomal surface, where TORC1 encounters its activator Rheb (reviewed in Shimobayashi & Hall, 2016). Upon amino acid withdrawal, Rags adopt an inactive conformation that no longer engages TORC1 but rather recruits the TSC complex to the lysosome to inhibit Rheb and thereby TORC1 signaling (Demetriades et al, 2014, 2016). Thus, shutting off TORC1 upon amino acid withdrawal is not simply a dissipation of upstream activation signals, but rather an active process. The importance of the TSC complex in dampening TORC1 signaling upon amino acid removal is highlighted by the fact that mouse embryonic fibroblasts lacking the TSC complex die upon amino acid removal due to unbridled TORC1 activity (Demetriades et al, 2014). A recent study from the Teleman lab (Tsokanos et al, 2016) provides insight on the mechanism mediating TORC1 inhibition upon amino acid withdrawal (Fig 1). In an RNAi screen in Drosophila S2 cells, the authors surprisingly identified the translation initiation factor eIF4A as an important inhibitor of TORC1 upon amino acid depletion. Upon eIF4A knockdown, cells fail to inactivate TORC1 signaling when amino acids are removed from the growth medium. eIF4A inhibits TORC1 in response to removal of different, non-overlapping subsets of amino acids, suggesting that the inhibition is not in response to the absence of a specific amino acid. Interestingly, eIF4A appears to inhibit TORC1 independently of its role in translation initiation, as knockdown of other translation initiation factors or pharmacological inhibition of translation does not affect downregulation of TORC1 signaling upon amino acid removal. The notion that eIF4A moonlights as a TORC1 inhibitor is further supported by the observation that a point mutation in eIF4A prevents TORC1 inhibition but not translation initiation. eIF4A appears to be a potent TORC1 inhibitor also in vivo since eIF4A mutant Drosophila larvae fail to inactivate