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

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. CUT&Tag of H3K27ac, H3K9ac, H3K27me3 in primed YFP+ NK cells from WT and ACLY KO mice.