Dynamic redox control of NF-κB through glutaredoxin-regulated S-glutathionylation of inhibitory κB kinase β

doi:10.1073/pnas.0603290103

Dynamic redox control of NF-κB through glutaredoxin-regulated S-glutathionylation of inhibitory κB kinase β

Departments of *Pathology and
^‡Chemistry, University of Vermont, Burlington, VT 05405;
^†Department of Respiratory Medicine, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, 62021 AZ, Maastricht, The Netherlands; and
^§Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 3, 2006 (received for review April 25, 2006)

Abstract

The transcription factor NF-κB, a central regulator of immunity, is subject to regulation by redox changes. We now report that cysteine-179 of the inhibitory κB kinase (IKK) β-subunit of the IKK signalosome is a central target for oxidative inactivation by means of S-glutathionylation. S-glutathionylation of IKK-β Cys-179 is reversed by glutaredoxin (GRX), which restores kinase activity. Conversely, GRX1 knockdown sensitizes cells to oxidative inactivation of IKK-β and dampens TNF-α-induced IKK and NF-κB activation. Primary tracheal epithelial cells from Glrx1-deficient mice display reduced NF-κB DNA binding, RelA nuclear translocation, and MIP-2 (macrophage inflammatory protein 2) and keratinocyte-derived chemokine production in response to LPS. Collectively, these findings demonstrate the physiological relevance of the S-glutathionylation–GRX redox module in controlling the magnitude of activation of the NF-κB pathway.

Footnotes

^¶To whom correspondence should be addressed at:
Department of Pathology, University of Vermont, HSRF Building, Room 216A, Burlington, VT 05405.
E-mail: yvonne.janssen{at}uvm.edu
Author contributions: N.L.R., A.v.d.V., D.E.M., and Y.M.W.J.-H. designed research; N.L.R., A.v.d.V., A.S.G., T.M., M.H., and J.H. performed research; N.L.R., C.P., N.H.H., and Y.-S.H. contributed new reagents/analytic tools; N.L.R., A.v.d.V., J.H., D.E.M., and Y.M.W.J.-H. analyzed data; and N.L.R., A.v.d.V., N.H.H., Y.-S.H., D.E.M., E.F.M.W., and Y.M.W.J.-H. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

IκB,

inhibitory κB;

IKK,

IκB kinase;

GRX,

glutaredoxin;

Bio-GEE,

biotinylated glutathione ethyl ester;

GSH,

glutathione;

GSSG,

glutathione disulfide;

RT,

room temperature.