Distinct sensor pathways in the hierarchical control of SNAT2, a putative amino acid transceptor, by amino acid availability

Russell Hyde, Emma L. Cwiklinski, Katrina MacAulay, Peter M. Taylor, Harinder S. Hundal

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    Abstract

    Mammalian nutrient sensors are novel targets for therapeutic intervention in disease states such as insulin resistance and muscle wasting; however, the proteins responsible for this important task are largely uncharacterized. Toaddress this issue we have dissected an amino acid (AA) sensor/effector regulon that controls the expression of the System A amino acid transporter-SNAT2-in mammalian cells, a paradigm nutrient-responsive process, and found evidence for the convergence of at least two sensor/effector pathways. During AA withdrawal, JNK is activated and induces the expression of SNAT2 in L6 myotubes by stimulating an intronic nutrient-sensitive domain. A sensor for large neutral AA (e.g. Tyr, Gln) inhibits JNK activation and SNAT2 up-regulation. Additionally, shRNA and transporter chimeras demonstrate that SNAT2 provides a repressive signal for gene transcription during AA sufficiency, thus echoing AA sensing by transceptor (transporter-receptor) orthologues in yeast (Gap1/Ssy1) and Drosophila (PATH). Furthermore, the SNAT2 protein is stabilized during AA withdrawal.

    Original languageEnglish
    Pages (from-to)19788-19798
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume282
    Issue number27
    DOIs
    Publication statusPublished - 6 Jul 2007

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