Among IκB ubiquitination blockers, the YopJ protein of the bacterial pathogen Yersinia deubiquitinates and stabilizes IκBα to prevent NF-κB nuclear translocation [96]. The small molecule R0196-9920 has been reported to inhibit IκBα ubiquitination and oral inflammation in mouse models [97, 98]. Yaron et al., [98] blocked TNFα-induced IκBα degradation by microinjecting phosphopeptides that corresponded to IκBα’s signal-dependent phosphorylation site. Presumably these phosphopeptides acted as competitive inhibitors for binding to the ubiquitin ligase complex essential to IκBα degradation. Inhibiting β-TrCP (the recognition subunit of the SCF E3 ligase complex) by specific RNAi treatment or by overexpression of dominant-negative β-TrCP mutants blocked NF-κB activity and sensitized breast cancer cells to chemotherapeutic agents [99]. Recently, A20 (TNFAIP3), a cytoplasmic zinc finger protein, was shown to inhibit NF-κB activation in the TNFR and TLR pathways. The ubiquitin editing property of A20 was shown to be essential for NF-κB inhibition [100].
