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Dynein light chain LC8 negatively regulates NF‐κB through the redox‐dependent interaction with IκBα
Author(s) -
Jung Yuyeon,
Kim Hojin,
Jeong Woojin
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb15-b
Subject(s) - phosphorylation , nf κb , chemistry , iκbα , microbiology and biotechnology , luciferase , thioredoxin , proteasome , recombinant dna , iκb kinase , p50 , redox , biochemistry , signal transduction , biology , enzyme , transfection , transcription factor , organic chemistry , gene
Dynein light chain LC8 was identified as a possible substrate of TRP14, a thioredoxin‐related protein of 14 kDa that inhibits TNFα‐induced NF‐κB activation in a previous study. It has been known to interact physically with the N‐terminal regulatory domain of NF‐κB inhibitor, IκBα. Here we show that LC8 binds to IκBα, protects it from phosphorylation by IKK and thereby inhibits NF‐κB activity. Recombinant LC8 protein inhibited the in vitro IKK activity, overexpression of LC8 suppressed NF‐κB activity stimulated by TNFα and depletion of LC8 by RNA interference augmented phosphorylation extent and degradation rate of IκBα, resulting in enhancement of NF‐κB activation induced by TNFα. Also LC8 attenuated NF‐κB activation stimulated other stimuli such as LPS and UV radiation or in other cellular background, suggesting that LC8 might serve as a general negative regulator of NF‐κB. Given that LC8 was identified as a possible substrate of TRP14 disulfide reductase, it is likely a target molecule of reactive oxygen species (ROS). Indeed it formed reversible intermolecular disulfide bond when cells were treated with H 2 O 2 or TNFα and Cys2 among three Cys residues (Cys2, Cys24 and Cys56) was revealed to be an oxidation site. Moreover interaction between LC8 and IκBα was decreased by treatment with H 2 O 2 or TNFα and in vitro reduction assay showed that Trx1 as well as TRP14 reduced oxidized LC8. Taken together, LC8 negatively regulates NF‐κB through the redox‐dependent interaction with IκBα and its redox status could be modulated by disulfide reductases such as TRP14 and Trx1.