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J. Biol. Chem., Vol. 283, Issue 35, 23863-23871, August 29, 2008

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Dynein Light Chain LC8 Negatively Regulates NF-B through the Redox-dependent Interaction with IB^*

From the Department of Life Science, Division of Life and Pharmaceutical Sciences, and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul 120-750, Korea

Redox regulation of nuclear factor B (NF-B) 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 (TNF)-induced NF-B activation, and we identified the dynein light chain LC8, which interacts with the NF-B inhibitor IB, as a potential substrate of TRP14. We now show the molecular mechanism by which NF-B activation is redox-dependently regulated through LC8. LC8 inhibited TNF-induced NF-B activation in HeLa cells by interacting with IB and thereby preventing its phosphorylation by IB kinase (IKK), without affecting the activity of IKK itself. TNF 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 IB. Butylated hydroxyanisol, an antioxidant, and diphenyleneiodonium, an inhibitor of NADPH oxidase, attenuated the phosphorylation and degradation of IB by TNF stimulation. In addition LC8 inhibited NF-B 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 IB 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.

Received for publication, April 22, 2008 , and in revised form, June 10, 2008.

^* This work was supported by Korea Research Foundation Grant KRF-2006-311-C00414 from the Korean government (the Ministry of Education and Human Resources Development), a Ewha Womans University Research Grant of 2005, Bio R & D Program Grant M10642040002-07N4204-00210 (to S.G.R.) and M10642040002-07N4204-00210 (to W. J.), National Core Research Center Program Grant R15-2006-020 through the Korea Science and Engineering Foundation funded by the Ministry of Education, Science and Technology, and funds from the Brain Korea 21 Scholars Program (to Y. J. and S. H. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed: Division of Life and Pharmaceutical Sciences, Ewha Womans University, Science Bldg. C, Rm. 102, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Korea. E-mail: rheesg{at}ewha.ac.kr. ³ To whom correspondence may be addressed: Dept. of Life Science, Division of Life and Pharmaceutical Sciences, Ewha Woman's University, Science Bldg. C, Rm. 207, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Korea. Tel.: 82-2-3277-4495; Fax: 82-2-3277-3760; E-mail: jeongw{at}ewha.ac.kr.

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