NFκB nuclear dynamics orchestrate inflammatory aging

Tabata, S.; Matsuda, K.; Nagai, K.; Izumi, Y.; Takahashi, M.; Motomura, Y.; Nagasato, A. I.; Shimma, S.; Moro, K.; Bamba, T.; Okada, M.

doi:10.1101/2023.04.18.536673

bioRxiv · 10.1101/2023.04.18.536673

NFκB nuclear dynamics orchestrate inflammatory aging

Tabata, S.·Matsuda, K.·Nagai, K.·Izumi, Y.·Takahashi, M.·Motomura, Y.·Nagasato, A. I.·Shimma, S.·Moro, K.·Bamba, T.·Okada, M.

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Abstract

Upregulation of nuclear factor {kappa}B (NF{kappa}B) signaling is a hallmark of aging and major cause of age-related chronic inflammation; however, its physiological functions and mechanisms remain unclear. By combining mathematical modeling and experiments, we show that dysfunction of negative feedback regulators of NF{kappa}B, I{kappa}B and A20, alters the NF{kappa}B nuclear dynamics from oscillatory to sustained, promoting cellular senescence by remodeling epigenetic regulation and metabolic landscape. Sustained NF{kappa}B activity by I{kappa}B downregulation enhanced inflammation- and senescence-associated gene expression through increased NF{kappa}B-DNA binding and slowed the cell cycle by upregulating purine catabolism via mTORC2/AKT pathways. Notably, I{kappa}B knockdown combined with A20 overexpression resulted in lower NF{kappa}B amplitude, cytokine expression, and SA-{beta}-gal activity than I{kappa}B knockdown alone. I{kappa}B downregulation is correlated with hypoxanthine phosphoribosyltransferase 1 (HPRT1) expression in the purine salvage pathway in aged mouse hearts. Our study suggests that nuclear NF{kappa}B homeostasis is critical for balancing purine metabolism associated with chronic inflammation and tissue aging.

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Tabata, S., Matsuda, K., Nagai, K., Izumi, Y., Takahashi, M., Motomura, Y., Nagasato, A. I., Shimma, S., Moro, K., Bamba, T., Okada, M.. 2023-04-18. NFκB nuclear dynamics orchestrate inflammatory aging. https://doi.org/10.1101/2023.04.18.536673

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