RMP limits innate immune activation in macrophages by inhibiting IKKβ activity in sepsis

Nuclear factor κB activity is a central component of inflammatory and innate immune responses. The inhibition of NF-κB signaling and of the IκB kinase complex is important for understanding the control of innate immunity. Here, we identified RNA polymerase II subunit 5 (RPB5)-mediating protein (RMP) as an inhibitor of the IKK complex, which thus inhibited NF-κB signaling in macrophages. In resting macrophages, RMP directly bound to the kinase domain of IKKβ and inhibited its activity by recruiting protein phosphatase 2A to the IKK complex. When mouse macrophages were treated with lipopolysaccharide, a TLR4 agonist that stimulates NF-κB signaling, RMP was phosphorylated by IKKβ at Ser439 and dissociated from the IKK complex, which further activated NF-κB signaling. Macrophage-specific deletion of Rmp reduced survival in mice due to an increased inflammatory response in experimental models of sepsis. This work demonstrates that RMP inhibits TLR4-induced NF-κB activation and exerts homeostatic control of innate immunity, and may be promising as a therapeutic target in the limiting of NF-κB signaling.