Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism

Li, M.; Jin, H.; Liu, Y.; Wang, Z.; Li, L.; Wang, T.; Wang, X.; Zhang, H.; Huo, B.; Yu, T.; Wang, S.; Zhao, W.; Liu, J.; Huang, P.; Cui, J.; Xia, X.

doi:10.1101/2024.11.11.622956

bioRxiv · 10.1101/2024.11.11.622956

Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism

Li, M.·Jin, H.·Liu, Y.·Wang, Z.·Li, L.·Wang, T.·Wang, X.·Zhang, H.·Huo, B.·Yu, T.·Wang, S.·Zhao, W.·Liu, J.·Huang, P.·Cui, J.·Xia, X.

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Abstract

Innate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by {beta}-glucan. ATAC-seq and RNA-seq analysis reveals that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF and NF-{kappa}B pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for S-adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions of Il6 and Tnf. Additionally, the tumor inhibition effect of {beta}-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM level through mTOR-FOXO3-GNMT axis.

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Li, M., Jin, H., Liu, Y., Wang, Z., Li, L., Wang, T., Wang, X., Zhang, H., Huo, B., Yu, T., Wang, S., Zhao, W., Liu, J., Huang, P., Cui, J., Xia, X.. 2024-11-11. Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism. https://doi.org/10.1101/2024.11.11.622956

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