Delineating role of ubiquitination on nuclear factor-kappa B pathway by a computational modeling approach

Mutant ubiquitin found in neurodegenerative diseases has been thought to hamper activation of transcription factor nuclear factor-kappa B (NF-κB) by inhibiting ubiquitin–proteasome system (UPS). It has been reported that ubiquitin also is involved in signal transduction in an UPS-independent manner. We used a modeling and simulation approach to delineate the roles of ubiquitin on NF-κB activation. Inhibition of proteasome complex increased maximal activation of IKK mainly by decreasing the UPS efficiency. On the contrary, mutant ubiquitin decreased maximal activity of IKK. Computational modeling showed that the inhibition effect of mutant ubiquitin is mainly attributed to decreased activity of UPS-independent function of ubiquitin. Collectively, our results suggest that mutant ubiquitin affects NF-κB activation in an UPS-independent manner.