MK2/p38/p53 negatively regulate basal IL-1β and non-canonical NF-κB signaling

Herr, S. M.; Stalkopf, D.; Padaszus, S.; Herbst, L. A.; Dörrie, A.; Niedenthal, R.; Ronkina, N.; Yakovleva, T.; Kotlyarov, A.; Gaestel, M.

doi:10.1101/2025.09.30.679163

bioRxiv · 10.1101/2025.09.30.679163

MK2/p38/p53 negatively regulate basal IL-1β and non-canonical NF-κB signaling

Herr, S. M.·Stalkopf, D.·Padaszus, S.·Herbst, L. A.·Dörrie, A.·Niedenthal, R.·Ronkina, N.·Yakovleva, T.·Kotlyarov, A.·Gaestel, M.

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Abstract

Interleukin (IL)-1{beta} is a pro-inflammatory cytokine implicated in sterile inflammation and tumor development. Investigating the role of MAPKAP kinase 2 (MK2) in IL-1{beta} processing, we found that Il1b mRNA and IL-1{beta} protein levels were elevated in resting MK2-knockout (KO) macrophages and in the serum of MK2/3-double-KO mice. This was linked to activation of the non-canonical NF-{kappa}B pathway in the absence of MK2 or its activator, p38. Rescue by MK2, its kinase-inactive mutant MK2K79R, or p38 suppressed this pathway and reduced Il1b expression. We also observed decreased basal protein levels of tumor suppressor p53 in MK2-or p38-deficient cells. Mechanistically, p53 interacts with mitochondrial caspase-3, promoting cleavage of RelB, thereby inhibiting non-canonical NF-{kappa}B signaling and subsequent Il1b and TP53 expression. These findings explain elevated basal IL-1{beta} levels in MK2-KO macrophages and uncover a new autoregulatory mechanism of TP53 expression. Additionally, they reveal a new mechanism that contributes to the long-discussed link between cancer and inflammation, wherein the tumor suppressor p53 inhibits cytokine production in parallel.

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Herr, S. M., Stalkopf, D., Padaszus, S., Herbst, L. A., Dörrie, A., Niedenthal, R., Ronkina, N., Yakovleva, T., Kotlyarov, A., Gaestel, M.. 2025-10-01. MK2/p38/p53 negatively regulate basal IL-1β and non-canonical NF-κB signaling. https://doi.org/10.1101/2025.09.30.679163

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