GAAC pathway limits autophagy to a light snack

Chen et al. reveal how cells coordinate their response to starvation so that they don’t degrade their components unnecessarily.

Cells respond to nutrient deprivation in a number of different ways. Low amino acid levels up-regulate the general amino acid control (GAAC) pathway, in which the transcription factor ATF4 induces the production of proteins that synthesize or import free amino acids. A lack of amino acids also inactivates the mTOR kinase and thereby up-regulates the autophagy pathway, in which cellular components are engulfed by autophagosomes and delivered to lysosomes to be degraded and recycled. However, cultured cells that only lack serum and the amino acid glutamine quickly reactivate mTOR and switch off autophagy.

Chen et al. found that these “mildly starving” cells had an increased ability to take up leucine and other amino acids from the surrounding medium. The absence of glutamine activated the GAAC pathway, up-regulating amino acid transporters such as the leucine importer SLC7A5. Knocking down SLC7A5 or the GAAC transcription factor ATF4 inhibited amino acid uptake and prevented mTOR reactivation, enhancing autophagy in these cells.

The GAAC pathway therefore prevents cells from degrading their own contents when sufficient nutrients are available externally to support cell survival. Senior author Li Yu is now interested in how this pathway might operate in vivo, where it could allocate scarce resources between tissues by favoring amino acid uptake in some cell types while permitting autophagy to occur in others.