Abstract #385

# 385
Role of amino acid transporters in amino acid sensing.
Peter M. Taylor*1, 1College of Life Sciences, University of Dundee, Dundee, UK.

Amino acid (AA) transporters have functional importance in nutrient sensing as well as in delivering tissue nutrient supplies. These transmembrane proteins mediate AA transfer and exchange between extracellular and various intracellular fluid compartments. AA transporters at the cell surface, particularly those for large neutral AA such as leucine, interact functionally with intracellular AA sensors and nutrient-signaling pathways which regulate metabolism; for example, the mTORC1 pathway which promotes cell growth and the GCN pathway activated by AA starvation. Upregulated expression of these AA transporter; for example, the leucine transporter SLC7A5 (System L1; LAT1), is required under some circumstances to initiate AA-dependent activation of the mTORC1 pathway. Transporter activity for leucine and other essential AA may be an important determinant of baseline insulin-sensitivity. Gastrointestinal-endocrine interactions contribute to dietary regulation of AA transporter expression and activity in the intestine. Certain AA transporters (e.g., SLC38A2, SLC38A9) may have dual receptor-transporter functions, operating as “transceptors” to sense extracellular (or intracellular) AA availability upstream of intracellular signaling pathways. SLC38A2 (System A; SNAT2) at the cell surface provides a repressive signal for gene transcription during AA sufficiency, thus echoing AA sensing by transceptor orthologs in yeast (e.g., Gap1). Expression and activity of SLC38A2 is upregulated by AA starvation by a mechanism dependent on both SLC38A2 gene transcription and enhanced stabilization of SLC38A2 protein. This forms part of an integrated cellular stress response to availability of nutrients, including unsaturated fatty acids which promote SLC38A2 protein degradation via the ubiquitin-proteasome system. SLC38A9 at the lysosomal membrane may act as the endosomal AA sensor for mTORC1 activation by glutamine and arginine. New opportunities for nutritional therapy may include targeting of AA transporters (or mechanisms which regulate their expression) to promote protein-anabolic signals for growth or retention of lean-tissue mass. Research funded by the Wellcome Trust, BBSRC UK and RERAD (Scottish Government).

Key Words: amino acid, membrane transport, cell signaling

Speaker Bio
Education:
1975-78    BSc Joint Hons: Chemistry/Zoology, Univ of Nottingham UK
1978-82    PhD by thesis in Comparative Physiology: Dept of Zoology, Univ of Leicester UK

Research:
My research (funded by The Wellcome Trust, BBSRC and Scottish Government (RESAS)) centres on the mechanisms of amino acid transport across mammalian cell membranes and their physiological functions in health and disease (including malnutrition). My principal focus is the role of the LAT1 (SLC7A5) amino acid transporter in sensing and signalling "availability" of amino acids to intracellular mechanisms (notably the mTORC1 pathway) which regulate protein synthesis, cell size and growth. We have developed a conditional knockout of LAT1 (SLC7A5) in mice to enable these studies. LAT1 also facilitates the actions of thyroid hormones (which are amino acid derivatives) by transporting them into target cells.

Scientific Publications:
Authored 104 publications receiving over 2350 citations (source http://www.researchgate.net)
Recent Publications
1) Pinilla J, Aledo JC, Cwiklinski E, Hyde R, Taylor PM & Hundal HS (2011) SNAT2 transceptor signalling via mTOR: a role in cell growth and proliferation? Front Biosci (Elite Ed). 3, 1289-99.
2) Loubière LS, Vasilopoulou E, Glazier JD, Taylor PM, Franklyn JA, Kilby MD, Chan SY (2012). Expression and function of thyroid hormone transporters in the microvillous plasma membrane of human term placental syncytiotrophoblast. Endocrinology 153:6126-35
3) Sinclair LV, Rolf J, Emslie E, Shi Y-B, Taylor PM, Cantrell DA (2013) Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nature Immunology 14, 500-8.
4) Taylor PM (2014) Role of amino acid transporters in amino acid sensing. Am. J. Clin. Nutr 99, 223S-230S.
5) Poncet N, Mitchell FE, Ibrahim AFM, McGuire VA, English G, Arthur JSC, Shi Y-B, Taylor PM (2014) The Catalytic Subunit of the System L1 Amino Acid Transporter (Slc7a5) Facilitates Nutrient Signalling in Mouse Skeletal Muscle PLOS One DOI: 10.1371/journal.pone.0089547.
6) Liu R, Iadevaia V, Averous J, Taylor PM, Zhang Z, Proud CG (2014) Impairing the production of ribosomal RNA activates mammalian target of rapamycin complex 1 signalling and downstream translation factors. Nucl Acid Res 42, 5083-96.
7) Nardi F, Hoffmann T, Stretton C, Cwiklinski E, Taylor PM, Hundal HS (2015) Proteasomal modulation of cellular SNAT2 (SLC38A2) abundance and function by unsaturated fatty acid availability. J Biol Chem doi: 10.1074/jbc.M114.625137