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Sci. Signal., 2 September 2008
Vol. 1, Issue 35, p. ec309
[DOI: 10.1126/scisignal.135ec309]

EDITORS' CHOICE

Redox Signaling Dynein Light Chain Connecting ROS to NF-{kappa}B

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

Tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-1β (IL-1β), and lipopolysaccharide (LPS), which are inflammatory mediators, trigger the production of reactive oxygen species (ROS) and activate the transcription factor nuclear factor {kappa}B (NF-{kappa}B). Jung et al. report that ROS contribute to the activation of NF-{kappa}B by promoting the oxidation and dimerization of the 8-kD dynein light chain called LC8. LC8 was previously identified as a substrate for TRP14, a disulfide reductase, which suggests that LC8 may be regulated by reversible oxidization. Addition of LC8 to an in vitro kinase assay showed that LC8 inhibited the phosphorylation of the NF-{kappa}B inhibitor I{kappa}B{alpha} by the kinase IKK, an event necessary for activation of NF-{kappa}B. LC8 did not inhibit IKK activity per se, but the association of LC8 with I{kappa}B{alpha} prevented its phosphorylation. Overexpression of LC8 inhibited NF-{kappa}B activation in response to TNF-{alpha}, IL-1β, and LPS. Cells in which LC8 was knocked down by siRNA methods showed increased abundance of Mn2+-dependent superoxide dismutase, which is encoded by an NF-{kappa}B target gene, compared with wild-type cells both in unstimulated cells and after TNF-{alpha} stimulation. Gel electrophoresis mobility shift assay revealed that a portion of LC8 was oxidized, so that it formed a disulfide-linked dimer in cells exposed to peroxide or TNF-{alpha}. In a pull-down assay with I{kappa}B{alpha}, reduced LC8 interacted to a greater extent than did oxidized LC8, and in cells exposed to TNF-{alpha} or peroxide, less endogenous LC8 coimmunoprecipitated with I{kappa}B{alpha} than in untreated cells. Inhibition of ROS production by addition of antioxidants or by inhibition of NADPH oxidases decreased the phosphorylation of I{kappa}B{alpha} in response to TNF-{alpha}. The authors propose that ROS-producing inflammatory ligands trigger the oxidation of LC8, which promotes its dissociation from I{kappa}B{alpha}, allowing I{kappa}B{alpha} to be phosphorylated and degraded, thereby releasing NF-{kappa}B from the inhibitory complex. TRP14 contributes to resetting the system by reducing LC8, which can then reassociate with I{kappa}B{alpha}.

Y. Jung, H. Kim, S. H. Min, S. G. Rhee, W. Jeong, Dynein light chain LC8 negatively regulates NF-{kappa}B through the redox-dependent interaction with I{kappa}B{alpha}. J. Biol. Chem. 283, 23863-23871 (2008). [Abstract] [Full Text]

Citation: N. R. Gough, Dynein Light Chain Connecting ROS to NF-{kappa}B. Sci. Signal. 1, ec309 (2008).



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