title: Dynamic redox control of NF-kappaB through glutaredoxin-regulated S-glutathionylation of inhibitory kappaB kinase beta.
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.
authors.affiliation: Department of Pathology and Chemistry, University of Vermont, Burlington, 05405, USA.
authors.forename: Niki L
authors.initials: NL
authors.lastname: Reynaert
authors.forename: Albert
authors.initials: A
authors.lastname: van der Vliet
authors.forename: Amy S
authors.initials: AS
authors.lastname: Guala
authors.forename: Toby
authors.initials: T
authors.lastname: McGovern
authors.forename: Milena
authors.initials: M
authors.lastname: Hristova
authors.forename: Cristen
authors.initials: C
authors.lastname: Pantano
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Heintz
authors.forename: John
authors.initials: J
authors.lastname: Heim
authors.forename: Ye-Shih
authors.initials: YS
authors.lastname: Ho
authors.forename: Dwight E
authors.initials: DE
authors.lastname: Matthews
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
mesh_terms: 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
chemical_list: 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