SIRT2 Mediates Integrated Stress Response by Deacetylating and Stabilizing 4EBP1 to Suppress Translation

The ability to alleviate nutrient stress, such as amino acid limitation, is crucial for cell survival. The mTORC1 complex and integrated stress response (ISR) are mechanisms that sense the availability of amino acids and regulate ribosomal protein synthesis. Here we have discovered a new SIRT2-mediated pathway, downstream of ISR, that senses the limitation of amino acids to regulate translation. Under amino acid deprivation, SIRT2 protein level is upregulated translationally by its upstream open reading frame (uORF). SIRT2 in turn suppresses global protein translation, which helps cells to survive amino acid limitation. Mechanistically, we identified eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4EBP1), which negatively regulates translation, as a substrate of SIRT2. SIRT2 deacetylates 4EBP1 at Lys69 and stabilizes 4EBP1 by protecting it from proteasomal degradation. Our study reveals a novel role for SIRT2 in regulating protein translation and a new regulatory mechanism of 4EBP1 in cells. Our study provides a better understanding of the intricate regulation of translation and may explain the known non-oncogene addiction role of SIRT2 in cancer cells.