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Regulation of NK effector function by ACLY-generated acetylation [RNA-Seq]

ABSTRACT: Natural Killer (NK) cells, integral to viral immunity and tumor clearance, are impacted by metabolism. A prior study revealed that cytokine stimulation boosts the citrate-malate shuttle and cytosolic acetyl-CoA through ATP citrate lyase (ACLY) in NK cells. Acetyl-CoA is vital for fatty acid synthesis and protein acetylation, including histones. To explore the role of ACLY in NK cell function, we generated an inducible NK-specific Acly knockout mouse model. ACLY loss in NKp46+ NK cells did not alter maturation or IFN-γ production in naïve NK cells. However, ACLY-deficient NK cells exhibited notable proliferation defects in IL-15-priming conditions, associated with impaired glycolysis. The stimulation and priming of NK cells through IL-15 is an important mechanism for enhancing effector and anti-tumor functions. Additionally, IL-15-primed ACLY-deficient NK cells showed reduced effector function in response to DAP12-associated activating receptors (NKG2D, Ly49H). This is because ACLY-deficient NK cells produce lower level of DAP12 during IL-15 priming, which was regulated in epigenetic level. These ACLY-driven deficiency was mostly rescued by acetate-generated acetyl-CoA, except glycolysis. Overall, these findings underscore ACLY's importance in NK cell proliferation and DAP12-driven effector functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE286450 | GEO | 2025/08/18

REPOSITORIES: GEO

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Regulation of NK effector function by ACLY-generated acetylation [CUT&Tag]

Project description:Natural Killer (NK) cells, integral to viral immunity and tumor clearance, are impacted by metabolism. A prior study revealed that cytokine stimulation boosts the citrate-malate shuttle and cytosolic acetyl-CoA through ATP citrate lyase (ACLY) in NK cells. Acetyl-CoA is vital for fatty acid synthesis and protein acetylation, including histones. To explore the role of ACLY in NK cell function, we generated an inducible NK-specific Acly knockout mouse model. ACLY loss in NKp46+ NK cells did not alter maturation or IFN-γ production in naïve NK cells. However, ACLY-deficient NK cells exhibited notable proliferation defects in IL-15-priming conditions, associated with impaired glycolysis. The stimulation and priming of NK cells through IL-15 is an important mechanism for enhancing effector and anti-tumor functions. Additionally, IL-15-primed ACLY-deficient NK cells showed reduced effector function in response to DAP12-associated activating receptors (NKG2D, Ly49H). This is because ACLY-deficient NK cells produce lower level of DAP12 during IL-15 priming, which was regulated in epigenetic level. These ACLY-driven deficiency was mostly rescued by acetate-generated acetyl-CoA, except glycolysis. Overall, these findings underscore ACLY's importance in NK cell proliferation and DAP12-driven effector functions.

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Project description:Our present study showed that lncRNA TINCR have impact on the ubiquitination-mediated degradation level of ACLY protein in nasopharyngeal carcinoma. Silencing of TINCR lead to downregulation of ACLY protein level. ACLY is a cytosolic homotetrameric enzyme catalyzing the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA, a precursor for lipid biosynthesis, including cholesterol, free fatty acid and phospholipid. Meanwhile, the cellular acetyl-CoA pool is also required for acetylation reactions that modify proteins such as histone acetylation, including Histone H3 acetylation K27 (H3K27ac). To select the shared genes that were regulated by TINCR and were in response to acetyl-CoA alteration, we conducted RNA-seq in HONE-1 cells with or without TINCR or ACLY silencing, as well as H3K27ac Chromatin Immunoprecipitation sequencing (ChIP-seq) in HONE-1 cells with or without ACLY silencing. We also performed CLIP-seq in HONE-1 and SUNE-1 cells to validate the TINCR-ACLY interaction and identify the binding sites of TINCR with ACLY.

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Project description:ATP-citrate lyase (ACLY) generates cytosolic acetyl-CoA for lipid synthesis and is a promising therapeutic target in disease contexts with altered lipid metabolism. Here, we developed inducible whole-body Acly knockout mice to determine the requirement for ACLY in normal tissue functions, uncovering its crucial role in skin homeostasis and barrier function. ACLY-deficient skin upregulates the acetyl-CoA synthetase ACSS2; and skin-specific double knockout (DKO) of Acly and Acss2 exacerbates skin abnormalities, with differential effects on two major lipid-producing skin compartments. While the epidermis is depleted of key barrier lipids, the sebaceous glands unexpectedly increase their lipid-rich sebum secretion, supplied in part by fatty acids released from adipose tissues. Accordingly, DKO mice rapidly lose fat mass, and dietary lipid supplementation partially rescues both the lipoatrophy and aberrant skin phenotypes. Thymic stromal lymphopoietin (TSLP), a cytokine with a role in regulating sebaceous glands, is overexpressed in DKO epidermis and thus may stimulate sebum secretion in response to deficient epidermal acetyl-CoA synthesis. Together, the data demonstrate that cytosolic acetyl-CoA synthesis in the skin both maintains local tissue homeostasis and influences systemic lipid partitioning and storage.

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