ACLY promotes NK cell effector function by regulating glycolysis and histone acetylation

Area of Science:

• Immunology
• Cell Biology
• Metabolism

Background:

• Natural killer (NK) cells are vital innate immune cells for antiviral and antitumor responses.
• ATP citrate lyase (ACLY) plays a key role in cellular metabolism, generating cytosolic acetyl-coenzyme A.
• The function of ACLY in NK cell immunity remains largely unexplored.

Purpose of the Study:

• To investigate the role of ATP citrate lyase (ACLY) in the functional capacity of natural killer (NK) cells.
• To elucidate the molecular mechanisms underlying ACLY's influence on NK cell activation and effector functions.

Main Methods:

• Utilized an inducible genetic mouse model to create ACLY-deficient NK cells.
• Assessed NK cell functions including glycolysis, proliferation, cytokine production, and cytotoxicity following IL-15 activation.
• Performed transcriptomic and epigenetic profiling to analyze gene expression and histone acetylation patterns.
• Investigated the impact of acetate supplementation on ACLY-deficient NK cell function.

Main Results:

• ACLY-deficient NK cells showed significant defects in glycolysis, proliferation, cytokine production, and cytotoxicity.
• ACLY deficiency specifically impaired responses mediated by DAP10 and DAP12 adapter proteins, altering their expression.
• Acetate supplementation rescued most functional defects in ACLY-deficient NK cells, restoring receptor function and expression.

Conclusions:

• ATP citrate lyase (ACLY) is essential for optimal natural killer (NK) cell effector functions.
• ACLY-derived cytosolic acetyl-coenzyme A is critical for regulating DAP10/12 expression and NK cell activation.
• Targeting ACLY or its metabolic products presents a potential strategy for modulating NK cell-based immunotherapies.