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Dynein light chain LC8 negatively regulates NF-κB through the redox-dependent interaction with IκBα
- Dynein light chain LC8 negatively regulates NF-κB through the redox-dependent interaction with IκBα
- Jung Y.; Kim H.; Sun H.M.; Sue G.R.; Jeong W.
- Ewha Authors
- 이서구; 정우진
- SCOPUS Author ID
- 이서구; 정우진
- Issue Date
- Journal Title
- Journal of Biological Chemistry
- Journal of Biological Chemistry vol. 283, no. 35, pp. 23863 - 23871
- SCIE; SCOPUS
- Document Type
- Redox regulation of nuclear factor κB (NF-κB) has been described, but the molecular mechanism underlying such regulation has remained unclear. We recently showed that a novel disulfide reductase, TRP14, inhibits tumor necrosis factor α (TNFα)-induced NF-κB activation, and we identified the dynein light chain LC8, which interacts with the NF-κB inhibitor IκBα, as a potential substrate of TRP14. We now show the molecular mechanism by which NF-κB activation is redox-dependently regulated through LC8. LC8 inhibited TNF α-induced NF-κB activation in HeLa cells by interacting with IκBα and thereby preventing its phosphorylation by IκB kinase (IKK), without affecting the activity of IKK itself. TNFα induced the production of reactive oxygen species, which oxidized LC8 to a homodimer linked by the reversible formation of a disulfide bond between the Cys2 residues of each subunit and thereby resulted in its dissociation from IκBα. Butylated hydroxyanisol, an antioxidant, and diphenyleneiodonium, an inhibitor of NADPH oxidase, attenuated the phosphorylation and degradation of IκBα by TNFα stimulation. In addition LC8 inhibited NF-κB activation by other stimuli including interleukin-1β and lipopolysaccharide, both of which generated reactive oxygen species. Furthermore, TRP14 catalyzed reduction of oxidized LC8. Together, our results indicate that LC8 binds IκBα in a redox-dependent manner and thereby prevents its phosphorylation by IKK. TRP14 contributes to this inhibitory activity by maintaining LC8 in a reduced state. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.
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