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The NAD-dependent deacetylase SIRT2 regulates T cell differentiation involved in tumor immune response.

ABSTRACT: Sirtuin 2 (SIRT2), an NAD+-dependent deacetylase, regulates multiple biologic and pathologic processes including mitosis, genomic integrity, cell homeostasis and tumorigenesis. However, the role of SIRT2 in the immune response to cancer remains largely elusive. In this study, we found significantly lower expression of SIRT2 in peripheral T lymphocytes from breast cancer patients when compared to normal individuals. Moreover, SIRT2 levels positively correlated with CD8⁺ effector memory T (T_EM) cells in breast cancer patients. In keeping with these findings, altered T cells differentiation manifested as decreased T_EM cells and increased naive T cells were observed in Sirt2 deficient mice. The upregulation of CD8⁺ T_EM by SIRT2 might attribute to the activation of aerobic oxidation as well as the inhibition of GSK3β acetylation in CD8⁺ T cells. Taken together, these results suggest that SIRT2 participate in tumor immune response by regulating T cell differentiation, which may provide novel insight for tumor prevention and immune therapy.

SUBMITTER: Jiang C

PROVIDER: S-EPMC7545715 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The NAD-dependent deacetylase SIRT2 regulates T cell differentiation involved in tumor immune response.

Jiang Cui C Liu Jingwei J Guo Min M Gao Xiaoxin X Wu Xuan X Bai Ning N Guo Wendong W Li Na N Yi Fei F Cheng Rong R Xu Hongde H Zhou Tingting T Jiang Bo B Sun Tao T Wei Shi S Cao Liu L

International journal of biological sciences 20201003 15

Sirtuin 2 (SIRT2), an NAD+-dependent deacetylase, regulates multiple biologic and pathologic processes including mitosis, genomic integrity, cell homeostasis and tumorigenesis. However, the role of SIRT2 in the immune response to cancer remains largely elusive. In this study, we found significantly lower expression of SIRT2 in peripheral T lymphocytes from breast cancer patients when compared to normal individuals. Moreover, SIRT2 levels positively correlated with CD8<sup>+</sup> effector memory ...[more]

PMID: 33061819

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Project description:RATIONALE: Hypertension can lead to podocyte damage and subsequent apoptosis, eventually resulting in glomerulosclerosis. Although alleviating podocyte apoptosis has clinical significance for the treatment of hypertensive nephropathy, an effective therapeutic target has not yet been identified. The function of Septin4, a pro-apoptotic protein and an important marker of organ damage, is regulated by post-translational modification (PTM). However, the exact role of Septin4 in regulating podocyte apoptosis and its connection to hypertensive renal damage remains unclear. OBJECTIVE: We investigated the function and underlying mechanism of Septin4 in AngII-induced hypertensive nephropathy to discover a theoretical basis for targeted treatment. METHODS AND RESULTS: Using transgenic Septin4-K174Q mutant mice treated with the antioxidant Tempol, we found that hyperacetylation of the K174 site of Septin4 exacerbates AngII induced hypertensive renal injury resulting from oxidative stress. Proteomics and western blotting assays indicated that Septin4-K174Q activates the cleaved-PARP1-cleaved-Caspase3 pathway. In Septin4-knockdown human renal podocytes, Septin4-K174R, which mimics deacetylation at K174, rescues podocyte apoptosis induced by AngII. We conclude that Septin4, when activated through acetylation of K174 (K174Q), promotes hypertensive renal injury. Immunoprecipitation and mass spectrometry analyses identified SIRT2 as a deacetylase that interacts with the Septin4 GTPase domain and deacetylates Septin4-K174. In Sirt2-deficient mice and SIRT2-knockdown renal podocytes, Septin4-K174 remains hyperacetylated and exacerbates hypertensive renal injury. By contrast, in Rosa26-Sirt2-Flag (SIRT2-TG) mice and SIRT2-knockdown renal podocytes re-expressing wild-type SIRT2, Septin4-K174 is hypoacetylated and mitigates hypertensive renal injury. CONCLUSION: Septin4-K174R, which mimics deacetylation by SIRT2, inhibits the cleaved-PARP1-cleaved-Caspase3 pathway. Septin4-K174R acts as a renal protective factor, mitigating AngII-induced hypertensive renal injury. These findings indicate that Septin4-K174 is a potential therapeutic target for the treatment of hypertensive renal injury.

Dataset Information

The NAD-dependent deacetylase SIRT2 regulates T cell differentiation involved in tumor immune response.

Publications

The NAD-dependent deacetylase SIRT2 regulates T cell differentiation involved in tumor immune response.

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