PATs and SNATs: Amino Acid Sensors in Disguise

Abstract

Solute Carriers (SLCs) are involved in the transport of substances across lipid bilayers, including nutrients like amino acids. Amino acids increase the activity of the microenvironmental sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) to promote cellular growth and anabolic processes. They can be brought in to cells by a wide range of SLCs including the closely related Proton-assisted Amino acid Transporter (PAT or SLC36) and Sodium-coupled Neutral Amino acid Transporter (SNAT or SLC38) families. More than a decade ago, the first evidence emerged that members of the PAT family can act as amino acid-stimulated receptors, or so-called "transceptors," connecting amino acids to mTORC1 activation. Since then, further studies in human cell models have suggested that other PAT and SNAT family members, which share significant homology within their transmembrane domains, can act as transceptors. A paradigm shift has also led to the PATs and SNATs at the surface of multiple intracellular compartments being linked to the recruitment and activation of different pools of mTORC1. Much focus has been on late endosomes and lysosomes as mTORC1 regulatory hubs, but more recently a Golgi-localized PAT was shown to be required for mTORC1 activation. PATs and SNATs can also traffic between the cell surface and intracellular compartments, with regulation of this movement providing a means of controlling their mTORC1 regulatory activity. These emerging features of PAT and SNAT amino acid sensors, including the transceptor mechanism, have implications for the pharmacological inhibition of mTORC1 and new therapeutic interventions.

Keywords: SLC36A1; SLC36A4; SLC38A9; SNAT2; amino acid transporter; mechanistic target of rapamycin (mTORC1); transceptor.

FIGURE 1

Transporters, pathetic flies and transceptors. (A) Schematic model of transporter switching between outward and inward facing conformations (upper and lower in gray), enabling molecules such as amino acids (AA) to be taken across lipid bilayers. The binding of such substrates is thought to stabilize an intermediate conformation (middle in red). Such transporters can function as symporters, co-transporting protons for some PATs and sodium ions for at least some SNATs. These ions determine the directionality of transport. (B) PAT amino acid transporter gene, pathetic, is required for normal growth in vivo. In comparison to normal controls (cont; middle fly) flies homozygous for the hypomorphic mutation, pathetic^KG06640 (KG/KG; lower fly) are small, or when heterozygous with a chromosomal deficiency (Df) removing the pathetic gene (KG/Df; upper fly) are even smaller. This small fly phenotype can be rescued by expression of a pathetic transgene. Mutations in other mTORC1 signaling pathway components also lead to small fly or small pupal phenotypes, for example, S6 kinase (Montagne et al., 1999) and mTOR (Zhang et al., 2000). This panel is reproduced with permission from the journal Development (Goberdhan et al., 2005). (C) Schematic model showing how PATs and SNATs may act as transceptors to activate mTORC1. Note that the molecular mechanism by which PATs and SNATs act as transceptors is currently unknown. The binding and/or translocation of amino acids or other substrates by PAT and SNAT transporters presumably induces specific conformational changes that generate a signal. Here, for illustration, we assume this signal is transmitted in the intermediate conformation (red; A), which may be formed during the transport cycle. The transceptor conformation facilitates the recruitment of membrane-bound sensing complex components (already assembled in a complex; Zoncu et al., 2011), cytoplasmic sensing complex components and mTORC1 constituents. This leads to the formation of a functional sensing complex that can respond to amino acid signals from the lumen of the intracellular compartment (where extracellular amino acids can rapidly accumulate; Zoncu et al., 2011) to activate mTORC1 signaling and drive cell growth.

FIGURE 2

Subcellular localisation of PAT and SNAT transporters: amino acid sensors in disguise. Schematic model showing PAT and SNAT amino acid transceptors, which can respond to specific amino acids in the lumen of intracellular compartments by activating mTORC1 and growth via a transport-independent mechanism. Note that the molecular mechanism by which PATs and SNATs act as transceptors is currently unknown. PAT and SNAT transporters have been identified in several different locations in cells, namely the plasma membrane, acidic late endosomes and lysosomes (LELs), and also the Golgi apparatus. In the transceptor model, the binding and/or translocation of specific amino acids or other substrates induces a conformational change that alters interactions with associated proteins and increases mTORC1 signaling. The amino acid sensing complexes associated with SNAT2 have not yet been characterized. Different transporters have been shown to shuttle between compartments; for example, in human cells, PAT1 (plasma membrane and LELs) and SNAT2 (Golgi and plasma membrane), thus modulating their mTORC1-regulatory activity.