Host organisms have evolved elaborate pathogen recognition and immune regulatory systems to effectively fend off bacterial invasions while evading unnecessary energy depletion and tissue damage caused by aberrant inflammation in the resting state. The transcription factor NF-κB serves as the central hub for coordinating inflammatory responses. However, the molecular mechanisms that precisely control its activation and suppression remain unclear.

In a study published in Science Immunology, a research team led by Prof. XIAO Wuhan from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences uncovered how occludin-ellipsoid protein 1 (OCEL1), a critical immune modulator, senses bacterial infection to regulate inflammatory responses, shedding new light on the intricate balance between host defense and immune homeostasis.

Researchers observed that human OCEL1 failed to stably express in Escherichia coli, while mouse Ocel1 did. Through sequence alignment and truncation analyses, they identified a unique N-terminal 30-amino-acid segment in human OCEL1. They restored stable expression by either mutating 81st/82nd prolines of palindromic proline-rich element (PPE) or deleting the element. Fusing the PPE motif to stable proteins caused them to destabilize, confirming PPE as a bacterial target.

Through mass spectrometry, researchers identified bacterial FK506-binding protein (FKBP) family isomerases as PPE binders. Overexpressing these FKBPs reduced wild-type OCEL1 levels via K48-linked ubiquitination, a process notably blocked by the inhibitor MG132. As this degradation did not affect PPE-mutated OCEL1, the results validated that OCEL1 breakdown was specifically FKBP-mediated.

Cell experiments showed that OCEL1 overexpression suppressed Lipopolysaccharide/Pseudomonas aeruginosa strain PAO1-induced proinflammatory cytokines, while its depletion amplified responses. OCEL1-deficient mice had severe hyperinflammation. Humanized mice with wild-type OCEL1 showed stronger inflammation than PPE-mutated ones during PAO1 infection. Mechanistically, OCEL1 bound NF-κB essential modulator (NEMO), leucine zipper domain, inhibiting TNF receptor associated factor 6-mediated lysine 63 ubiquitination, effectively suppressing NF-κB activation during resting states.

This study uncovers a novel "enzyme activity-sensing" pathogen recognition mode, expanding the understanding of host-pathogen interactions. It clarifies a function for bacterial FKBP isomerases: the targeted degradation of OCEL1, revealing OCEL1-NEMO axis as a fine-tuned NF-κB regulator. The findings provide therapeutic targets. PPE-FKBP inhibitors enhance anti-infection responses, while stabilized OCEL1 mitigates inflammatory damage.