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

Publication date: 5 June 2018
Source:Cell Reports, Volume 23, Issue 10
Author(s): Nan Zhang, Xin Yang, Fengjie Yuan, Luyao Zhang, Yanan Wang, Lina Wang, Zebin Mao, Jianyuan Luo, Hongquan Zhang, Wei-Guo Zhu, Ying Zhao
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.

Graphical abstract

Teaser

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.


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