Deletion of Glycogen Synthase Kinase 3 Beta Reprograms NK Cell Metabolism

Area of Science:

• Immunology
• Cell Biology
• Metabolism

Background:

• Overexpression of glycogen synthase kinase 3 beta (GSK3β) is linked to impaired natural killer (NK) cell function and metabolism in acute myeloid leukemia (AML).
• Previous studies showed GSK3β inhibition improved NK cell activity, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the specific role of GSK3β in regulating NK cell metabolism and function.
• To elucidate the mechanisms of GSK3β-mediated dysfunction in NK cells.

Main Methods:

• Utilized CRISPR gene editing to delete the GSK3B gene in NK cells.
• Expanded knockout (KO) and wild-type (WT) NK cells and performed transcriptional and functional analyses.
• Assessed NK cell cytotoxicity, maturation (CD57 expression), cytokine production, gene expression, and cellular energetics.

Main Results:

• GSK3B deletion did not affect NK cell cytotoxicity, maturation, or cytokine production.
• GSK3B-KO NK cells showed significant alterations in genes related to rRNA processing, cell proliferation, and metabolism.
• GSK3B-KO NK cells exhibited 150% higher spare respiratory capacity, indicating enhanced metabolic fitness.
• Genes downregulated in GSK3B-KO NK cells were upregulated in GSK3β-overexpressing NK cells from AML patients.

Conclusions:

• GSK3β plays a critical role in regulating NK cell metabolism, rather than cytotoxicity or maturation.
• Loss of GSK3β leads to metabolic reprogramming and improved metabolic fitness in NK cells.
• These findings highlight GSK3β as a potential therapeutic target for modulating NK cell metabolism in AML.