A New Regulatory Mechanism of NF-κB Activation by I-κBβ in Cancer Cells

Transglutaminase 2 (TGase 2) catalyzes covalent isopeptide bond formation between glutamine and lysine residues. Recently, we reported that TGase 2 activates nuclear factor-kappa B (NF-kappa B) by depleting inhibitor of NF-kappa B alpha (I-kappa B alpha) levels via polymer formation. Furthermore, TGase 2 expression synergistically increases NF-kappa B activity with canonical pathway. The major I-kappa B proteins such as I-kappa B alpha and I-kappa KB beta resemble each other in both primary sequence and tertiary structure. However, I-kappa KB beta does not degrade fully, while I-kappa B alpha degrades immediately in response to most stimuli. We found that I-kappa KB beta does not contain any of the previously identified TGase 2 target sites. In this study, both an in vitro cross-linking assay and a TGase 2 transfection assay revealed that I-kappa B beta is independent from TGase 2-mediated polymerization. Furthermore, increased I-kappa B beta expression reversed NF-kappa B activation in cancer cells, compensating for the loss of I-kappa B alpha via TGase 2 polymerization. (C) 2008 Elsevier Ltd. All rights reserved.