Mallory-Denk-bodies (MDBs) are hepatic inflammation-associated protein aggregates. Similar protein aggregation in neurodegenerative diseases also triggers inflammation and NF-κB-activation by an as yet uncharacterized non-canonical mechanism. Herein, employing an MDB-inducing cell model, we
uncovered a novel mechanism for NF-κB-activation via cytoplasmic IκBα-sequestration into
insoluble aggregates. Additionally, through affinity pull-down, proximity labeling, and other proteomic approaches, we identified 10 proteins that interact with IκBα and form insoluble aggregates upon ZnPP- treatment.
This novel mechanism would account for the protein aggregate-induced inflammation.