SIRT2 is one of the mammalian NAD+-dependent lysine deacylase. It has attracted growing research interest due to the broad deacylation substrate scope and diverse cellular functions. There have been more than 40 deacylation substrates of SIRT2 reported, which mechanically contributes to the regulatory role of SIRT2 in cell cycle regulation, metabolism, pathogen-host interaction, and cancer. Although many cellular functions of SIRT2 are reported, the current biological understanding of SIRT2 is not coherent and lack principles that can connect and organize various observations. Although targeting SIRT2 with small molecules has been demonstrated to have therapeutic potentials, the lack of a deeper understanding of the function of SIRT2 has slowed down the utilization of SIRT2 modulators to treat human diseases. My projects started with investigating the role of SIRT2 in the context of stress response. We aimed to find stress conditions that upregulate SIRT2 protein level. We hypothesized that this would allow us to highlight SIRT2 functions that are highly needed during stress responses. Using this strategy, we observed the alteration of SIRT2 protein level under amino acid depletion, which is translationally regulated through upstream open reading frames (uORF) as part of integrated stress response (ISR) mechanism. Due to high proliferation rate and abnormal vasculature, cancer cells often experience nutrient limitation stress. SIRT2 ablation sensitizes cancer cell to amino acid depletion and thus contributes to the anticancer activities of SIRT2 inhibitors. Mechanistically, stress induced SIRT2 suppresses mTORC1 activity through deacetylating JNK, which leads to the suppression of global translation. Accordingly, SIRT2 coordinates the crosstalk between mTORC1 and ISR to help cancer cells adapt to and survive amino acid limitation stress. Additionally, we found that SIRT2 is transcriptionally upregulated under Golgi stress, which is induced by certain bacterial infection, such as Shigella. SIRT2 significantly suppresses Shigella invasion in cells and in vivo. Sirt2 knockout mice, though displaying no obvious abnormality under basal conditions, behave much poorly during pathogen infection. Mechanistically, stress-induced SIRT2 works as a defatty-acylase to directly remove the lysine fatty acylation on host proteins that are induced by IcsB, a Shigella effector protein. Lysine fatty acylation is a novel protein post-translational modification with few substrates reported. Our findings not only discover more physiological substrates of SIRT2, but more importantly, provide a clear physiological purpose for lysine fatty acylation in the context of pathogen-host interaction.