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-kappaB) by depleting inhibitor of NF-kappaBalpha (I-kappaBalpha) levels via polymer formation. Furthermore, TGase 2 expression synergistically increases NF-kappaB activity with canonical pathway. The major I-kappaB proteins such as I-kappaBalpha and I-kappaBbeta resemble each other in both primary sequence and tertiary structure. However, I-kappaBbeta does not degrade fully, while I-kappaBalpha degrades immediately in response to most stimuli. We found that I-kappaBbeta 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-kappaBbeta is independent from TGase 2-mediated polymerization. Furthermore, increased I-kappaBbeta expression reversed NF-kappaB activation in cancer cells, compensating for the loss of I-kappaBalpha via TGase 2 polymerization.
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