# SEA and GATOR 10 Years Later
## 5 Function of the SEA and GATOR in Nutrient Sensing and Responding
### SEACIT and Amino Acid Sensing in Yeast  
Amino acid sensing in yeast differs significantly from the mammalian system (Figure 3B). SESTRINs, CASTOR1 and SAMTOR are not conserved in _S. cerevisiae_ and S. pombe_, which presumes that the interaction of these amino acid sensors with GATOR complexes arose later in the evolution. Nevertheless, Npr2 does participate in methionine sensing in _S. cerevisiae_, but in a very different way than in mammals. Under normal growth conditions, Ppm1p methyltransferase methylates two subunits of yeast protein phosphatase 2A (PP2A), which promotes Nrp2 dephosphorylation, TORC1 activation and suppression of autophagy [103]. Low methionine level leads to a decreased SAM, which blocks PP2A methylation and its phosphatase activity. As a result, Npr2 accumulates in phosphorylated form, which most probably changes the integrity of the SEACIT complex due to increased interaction between phosphorylated Npr2 and Im11/Sea1 [9]. Therefore, SEACIT is no longer able to repress TORC1 effectively, resulting in autophagy activation. Interestingly, Npr2-deficient yeast grown in a minimal medium, containing ammonium as a sole nitrogen source and lactate as a nonfermentable carbon source, metabolize glutamine into nitrogen-containing metabolites and maintain high SAM concentrations [104]. As in mammals, yeast also have amino acid sensing pathways parallel to SEA-GTR signaling [105]. For example, Pib2, which resides at the vacuole membrane, interacts with TORC1 complex in a glutamine-sensitive manner, suggesting that Pib2 acts as a part of a putative glutamine sensor [64]. Although both Pib2 and EGO are required for TORC1 tethering to the vacuolar membrane and its activation, they form different complexes with TORC1, ruling out a possibility that the SEA complex can participate in Pib2-dependent amino acid sensing. Even if Pib2 does not have apparent ortholog in mammals, PLEKHF1 protein shares high sequence similarity with Pib2 domains, important for TORC1 activation. However, PLEKHF1 is not involved in the glutamine-dependent regulation of mTORC1 [65]. In addition, Whi2, localized at the cell periphery, specifically senses low amino acid levels in general and leucine levels in particular, and suppresses TORC1 activity independently of the SEA complex [106; 107]. The Whi2 homologue in mammals, KCTD11, acts as a negative regulator of mTORC1 during amino acid deprivation [106]. All these recent findings demonstrate that amino acid sensing mechanisms are way more diverse, because not only amino acids themselves, but also their metabolites can be sensed in a RAG-dependent, RAG-independent and cell-specific manner. Many questions about amino acid sensing ultimately related to SEA and GATOR functions remain unanswered. Does every amino acid have its own sensor? Will all the sensors that work through RAGs interact with GATORs? What are the determinants of the interaction of amino acid sensors with one or another GATOR complex? In other words, why do SESTRIN2 and CASTOR1 interact with GATOR2, and SAMTOR with GATOR1? What are the factors that determine sensing of the same amino acid by different sensors? For example, why does leucine need three sensors (SESTRIN2, SAR1B and LARS1) that function in the same cell types, in the same subcellular location (cytosol), through the same pathway (RAG-dependent)? leucine can also signal through its catabolite acetyl-CoA and activate mTORC1 via EP-300-mediated acetylation of RAPTOR [102]. Can other amino acids signal both themselves and their metabolites through different sensors? For example, the methionine metabolite SAM is sensed by SAMTOR, does a methionine sensor exist? Amino acid sensing also happens at Golgi, where GATORs, SESTRINS, CASTOR1 and SAMTOR have not been found thus far. How is amino acid sensing is achieved at Golgi? What is the repertoire of cell-type specific sensors? The primary role of aminoacyl tRNA synthetases is binding to cognate amino acids and their attachment onto appropriate tRNAs.