The inactivation of the prototype NF-kB inhibitor, IkBa, occurs through a series of ordered processes including phosphorylation, ubiquitin conjugation and proteasome-mediated degradation (Ub-Pr). We previously detected a 97 kDa protein co-immunoprecipitated with IkBa, and identified it as the valosin-containing protein (VCP), a member of the AAA ATPases a ssociated with a variety of cellular activities) family. Biochemical studies demonstrated that phosphorylation and ubiquitination of IkBa are required for its binding to VCP, which subsequently is required for the degradation of IkBa. Furthermore, VCP copurified with the 26S proteasome in highly purified proteasome preparations. We recently generated a panel of antisera against VCP and found that VCP preferentially associated with the uniquitinated forms of IkBa, and VCP co-immunoprecipitated with other subunits of the proteasome. These results strongly suggest that VCP provides a functional and physical link between the IkBa and the proteasome in Ub-Pr mediated degradation pathway. We propose a model for IkBa inactivation in which ubiquitinated IkBa conjugates become physically associated with VCP which displaces the NF-kB dimer, thus releasing the dimer for translocation into the nucleus. The ubiquitinated IkBa is then chaperoned to the 26S proteasome for degradation. Currently, we are searching for other Ub-Pr substrates that are also chaperoned by VCP, and several proteins have been identified.
| Wang, Qing; Song, Changcheng; Li, Chou-Chi H (2004) Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. J Struct Biol 146:44-57 |
| Yang, Yili; Li, Chou-Chi H; Weissman, Allan M (2004) Regulating the p53 system through ubiquitination. Oncogene 23:2096-106 |
| Wang, Qing; Song, Changcheng; Li, Chou-Chi H (2003) Hexamerization of p97-VCP is promoted by ATP binding to the D1 domain and required for ATPase and biological activities. Biochem Biophys Res Commun 300:253-60 |
| Song, Changcheng; Wang, Qing; Li, Chou-Chi H (2003) ATPase activity of p97-valosin-containing protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity. J Biol Chem 278:3648-55 |
| Wang, Qing; Song, Changcheng; Yang, Xiaoyi et al. (2003) D1 ring is stable and nucleotide-independent, whereas D2 ring undergoes major conformational changes during the ATPase cycle of p97-VCP. J Biol Chem 278:32784-93 |
