Dynamic redox control of NF-kappaB through glutaredoxin-regulated S-glutathionylation of inhibitory kappaB kinase beta.
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.
Reynaert
Niki L
NL
Department of Pathology and Chemistry, University of Vermont, Burlington, 05405, USA.
van der Vliet
Albert
A
Guala
Amy S
AS
McGovern
Toby
T
Hristova
Milena
M
Pantano
Cristen
C
Heintz
Nicholas H
NH
Heim
John
J
Ho
Ye-Shih
YS
Matthews
Dwight E
DE
Wouters
Emiel F M
EF
Janssen-Heininger
Yvonne M W
YM
D000818:Animals; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D003545:Cysteine / Q000378:metabolism; D054477:Glutaredoxins; D005978:Glutathione / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015846:Monokines / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010088:Oxidoreductases / Q000172:deficiency / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects; D013434:Sulfenic Acids / Q000378:metabolism
D054426:Chemokine CXCL2; D018925:Chemokines; C516006:Glrx protein, mouse; D054477:Glutaredoxins; D008070:Lipopolysaccharides; D015846:Monokines; D016328:NF-kappa B; D021122:Protein Subunits; D013434:Sulfenic Acids; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D051550:I-kappa B Kinase; D005978:Glutathione; D003545:Cysteine