Increased Amino Acid Uptake Supports Autophagy-Deficient Cell Survival upon Glutamine Deprivation

Autophagy is a protein degradation process by which intracellular materials are recycled for energy homeostasis. However, the metabolic status and energy source of autophagy-defective tumor cells are poorly understood. Here, our data show that amino acid uptake from the extracellular environment is increased in autophagy-deficient cells upon glutamine deprivation. This elevated amino acid uptake results from activating transcription factor 4 (ATF4)-dependent upregulation of AAT (amino acid transporter) gene expression. Furthermore, we identify SIRT6, a NAD+-dependent histone deacetylase, as a corepressor of ATF4 transcriptional activity. In autophagy-deficient cells, activated NRF2 enhances ATF4 transcriptional activity by disrupting the interaction between SIRT6 and ATF4. In this way, autophagy-deficient cells exhibit increased AAT expression and show increased amino acid uptake. Notably, inhibition of amino acid uptake reduces the viability of glutamine-deprived autophagy-deficient cells, but not significantly in wild-type cells, suggesting reliance of autophagy-deficient tumor cells on extracellular amino acid uptake. [Display omitted] •Autophagy deficiency enhances amino acid uptake during glutamine starvation•SIRT6 represses amino acid transporter expression in an autophagy-dependent manner•Amino acid uptake promotes survival of autophagy-deficient cells upon Gln depletion Zhang et al. show that amino acid uptake from the extracellular environment is increased in autophagy-deficient cells upon glutamine deprivation, resulting from increased amino acid transporter expression. Inhibition of amino acid uptake reduces the viability of glutamine-deprived autophagy-deficient cells.