SIRT2 MEDIATES INTEGRATED STRESS RESPONSE BY SUPPRESSING PROTEIN TRANSLATION
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Cells face various stresses, and the ability to alleviate stress is crucial to cells’ health and survival. Protein translation is an important and intricate process, which is tightly regulated by many factors in response to the environment. This thesis explores how Sirtuin 2 (SIRT2) responds to amino acid deprivation and regulates protein translation by deacetylating multiple substrates. In chapter 1, I will introduce background information on acetylation, sirtuins, and signaling pathways that are relevant to this thesis. Specifically, I will dive into the mechanism of integrated stress response and mechanistic target of rapamycin (mTOR) pathways and how SIRT2 is related to stress response. Chapter 2 reveals how SIRT2 responds to amino acid deprivation stress by deacetylating and stabilizing eukaryotic translation initiation factor 4E (eIF4E)-binding protein1 (4EBP1) to suppress protein translation. We have discovered that SIRT2 is upregulated translationally under amino acid deprivation. Moreover, we have identified 4EBP1 as a novel substrate of SIRT2. SIRT2 deacetylates 4EBP1 at lysine residue K69, which stabilizes 4EBP1 by preventing its ubiquitination and proteasomal degradation, leading to decreased protein translation given that 4EBP1 has an inhibitory effect on translation. Chapter 3 focuses on another substrate of SIRT2, Rheb, that also contributes to SIRT2’s regulation on translation. Rheb is involved in the activation of mTOR complex 1 (mTORC1). We have uncovered that SIRT2 deacetylates Rheb at lysine residue K151, leading to increased ubiquitination and degradation. As a result of the decreased level of Rheb, translation is downregulated. Chapter 4 is a summary of the thesis and contains preliminary results for a future direction.