Abstract
The ability of the innate immune system to distinguish between low level microbial presence and invasive pathogens is fundamental for immune homeostasis and immunity. However, the molecular mechanisms underlying threat discrimination by innate immune cells are not clearly defined. Here we describe the integration of the NF-ĸB and MAPK pathways in the nucleus by the IĸB protein BCL-3 and the MAP3K TPL-2. Our data reveals that TPL-2 is a nucleocytoplasmic shuttling protein and demonstrates that the nucleus is the primary site for TPL-2 ubiquitination and proteasomal degradation. BCL-3 promotes TPL-2 degradation through interaction in the nucleus. As a consequence, Bcl3-/- macrophages have increased TPL-2 stability and MAPK activity following TLR stimulation. The enhanced stability of TPL-2 in Bcl3-/- macrophages lowers the MAPK activation threshold and the level of TLR ligand required to initiate an inflammatory response. This study establishes the nucleus as a key regulatory site for TLR-induced MAPK activity and identifies BCL-3 as a regulator of the cellular decision to initiate inflammation