4.6 Article

Dynein light chain LC8 negatively regulates NF-κB through the redox-dependent interaction with IκBα

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 283, 期 35, 页码 23863-23871

出版社

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M803072200

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资金

  1. Korean government (the Ministry of Education and Human Resources Development) [KRF-2006-311C00414]
  2. Ewha Womans University Research
  3. Bio R D Program [M10642040002-07N4204-00210]
  4. National Core Research Center Program [R15-2006-020]
  5. Korea Science and Engineering Foundation
  6. Brain Korea 21 Scholars Program
  7. Ministry of Education, Science and Technology
  8. National Research Foundation of Korea [2006-05121, R09-2006-000-10002-0, R15-2006-020-01001-0, 2006-311-C00414, 2006-05119] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

向作者/读者索取更多资源

Redox regulation of nuclear factor kappa B (NF-kappa 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 alpha (TNF alpha)-induced NF-kappa B activation, and we identified the dynein light chain LC8, which interacts with the NF-kappa B inhibitor I kappa B alpha, as a potential substrate of TRP14. We now show the molecular mechanism by which NF-kappa B activation is redox-dependently regulated through LC8. LC8 inhibited TNF alpha-induced NF-kappa B activation in HeLa cells by interacting with I kappa B alpha and thereby preventing its phosphorylation by I kappa B kinase (IKK), without affecting the activity of IKK itself. TNF alpha induced the production of reactive oxygen species, which oxidized LC8 to a homodimer linked by the reversible formation of a disulfide bond between the Cys(2) residues of each subunit and thereby resulted in its dissociation from I kappa B alpha. Butylated hydroxyanisol, an antioxidant, and diphenyleneiodonium, an inhibitor of NADPH oxidase, attenuated the phosphorylation and degradation of I kappa B alpha by TNF alpha stimulation. In addition LC8 inhibited NF-kappa B activation by other stimuli including interleukin-1 beta and lipopolysaccharide, both of which generated reactive oxygen species. Furthermore, TRP14 catalyzed reduction of oxidized LC8. Together, our results indicate that LC8 binds I kappa B alpha 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.

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