Dynamic redox control of NF-kappaB through glutaredoxin-regulated S-glutathionylation of inhibitory kappaB kinase beta

N.L. Reynaert, A. van der Vliet, A.S. Guala, T. McGovern, M.J. Hristova-Dijkstra, C. Pantano, N.H. Heintz, J. Heim, Y.S. Ho, D.E. Matthews, E.F. Wouters, Y. Janssen-Heininger

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Abstract

The transcription factor NF-kappaB, a central regulator of immunity, is subject to regulation by redox changes. We now report that cysteine-179 of the inhibitory kappaB kinase (IKK) beta-subunit of the IKK signalosome is a central target for oxidative inactivation by means of S-glutathionylation. S-glutathionylation of IKK-beta Cys-179 is reversed by glutaredoxin (GRX), which restores kinase activity. Conversely, GRX1 knockdown sensitizes cells to oxidative inactivation of IKK-beta and dampens TNF-alpha-induced IKK and NF-kappaB activation. Primary tracheal epithelial cells from Glrx1-deficient mice display reduced NF-kappaB 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-kappaB pathway.
Original languageEnglish
Pages (from-to)13086-13091
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number35
DOIs
Publication statusPublished - 1 Jan 2006

Cite this

Reynaert, N. L., van der Vliet, A., Guala, A. S., McGovern, T., Hristova-Dijkstra, M. J., Pantano, C., Heintz, N. H., Heim, J., Ho, Y. S., Matthews, D. E., Wouters, E. F., & Janssen-Heininger, Y. (2006). Dynamic redox control of NF-kappaB through glutaredoxin-regulated S-glutathionylation of inhibitory kappaB kinase beta. Proceedings of the National Academy of Sciences of the United States of America, 103(35), 13086-13091. https://doi.org/10.1073/pnas.0603290103