Mutant ubiquitin found in neurodegenerative diseases has been thought to hamper activation of transcription factor nuclear factor-kappa B (NF-kappa B) 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-kappa B activation Inhibition of proteasome complex increased maximal activation of IKK mainly by decreasing the UPS efficiency Oil 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-kappa B activation in an UPS-independent manner. (C) 2009 Elsevier Inc All rights reserved