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

Investigating the role of MAPKAP kinase 2 (MK2) in IL-1β processing, we found that Il1b mRNA and IL-1β 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-κB pathway in the absence of MK2 or its activator, p38α.

Rescue by MK2, its kinase-inactive mutant MK2K79R, or p38α suppressed this pathway and reduced Il1b expression. We also observed decreased basal protein levels of tumor suppressor p53 in MK2- or p38α-deficient cells. Mechanistically, p53 interacts with caspase-3, promoting cleavage of RelB, thereby inhibiting non-canonical NF-κB signaling and subsequent Il1b and TP53 expression.