Involvement of Ymer in suppression of NF-κB activation by regulated interaction with lysine-63-linked polyubiquitin chain

It is known that the cytoplasmic zinc finger protein A20 functionally dampens inflammatory signals and apoptosis via inhibition of NF-κB activation and biochemically acts as a unique ubiquitin-modifying protein with deubiquitinating activity and ubiquitin ligase activity. However, the molecular mechanisms of A20-modulated signal transduction that influence normal immune responses or tumor immunity have not been fully elucidated. Using a yeast two-hybrid system to search for proteins interacting with A20, we identified one novel binding protein, Ymer. Ymer, which has been reported to be highly phosphorylated on tyrosine residues via EGF stimulation, bound to lysine (K)-63-linked polyubiquitin chain on receptor-interacting serine/threonine-protein kinase 1 (RIP1), which is essential for NF-κB signaling in collaboration with A20. A luciferase assay showed that NF-κB signaling was down-regulated by overexpression of Ymer, whereas knock-down of Ymer up-regulated NF-κB signaling even without stimulation. These findings demonstrate that Ymer is likely to be a negative regulator for the NF-κB signaling pathway.