Human OCEL1 senses bacterial infection to unlock inflammatory responses

Processes that control tissue inflammation are essential to restore homeostasis after infection. The transcription factor NF-κB plays a central role in coordinating inflammation, but the mechanisms that regulate NF-κB signaling are not fully understood. Here, we identify <i>OCEL1</i> (<i>occludin/ELL domain containing 1</i>) as a negative regulator of NF-κB signaling. In the absence of infection, human OCEL1 bound to the LZ domain of NEMO (NF-κB essential modulator) and inhibited TRAF6-mediated K63-linked polyubiquitination, suppressing NF-κB signaling. During infection, OCEL1-mediated negative regulation of NF-κB signaling was impaired by FK506-binding protein bacterial peptidyl-prolyl cis/trans isomerases, which bound to OCEL1 in an amino-terminal palindromic proline-rich element (PPE) and promoted its degradation. Mice expressing a mutant version of the human <i>OCEL1</i> PPE had dampened inflammation and increased susceptibility to <i>Pseudomonas aeruginosa</i> infection. Thus, the PPE of human OCEL1 senses bacterial infection, and its degradation releases the suppression of NF-κB signaling and promotes inflammation.