Inhibitor of growth 4 induces NFκB/p65 ubiquitin-dependent degradation.

As a tumor suppressor protein, the inhibitor of growth 4 (ING4) has an important role in many cellular processes including cell cycle progression, proliferation, apoptosis, DNA damage response, tumor angiogenesis and contact inhibition. Here, we report that ING4 functions as an E3 ubiquitin ligase to induce nuclear factor-κB (NFκB)/p65 degradation. The plant homeodomain finger of ING4 interacted with p65 to undergo robust ubiquitination and degradation. ING4 bound to p65 and delivered the Lys-48-linked polyubiquitin to Lys-62 residue of p65, leading to ubiquitination of p65 and degradation. Lys-62 residue of p65 was required for ING4-mediated ubiquitination of p65 and degradation. Further analysis shows that C239 of ING4 was critical for ING4-induced p65 degradation. These findings demonstrate that ING4 acts as an E3 ubiquitin ligase to induce ubiquitination of p65 and degradation, which is critical to terminate NFκB activation.