Regulatory Role for a Novel Human Thioredoxin Peroxidase in NF-κB Activation

Reduction-oxidation (redox) plays a critical role in NF-κB activation. Diverse stimuli appear to utilize reactive oxygen species (e.g. hydrogen peroxide) as common effectors for activating NF-κB. Antioxidants govern intracellular redox status, and many such molecules can reduce H2O2. However, functionally, it does appear that different antioxidants are variously selective for redox regulation of certain transcription factors such as NF-κB. For NF-κB, thioredoxin has been described to be a more potent antioxidant than either glutathione orN-acetylcysteine. Thioredoxin peroxidase is the immediate enzyme that links reduction of H2O2 to thioredoxin. Several putative human thioredoxin peroxidases have been identified using recursive sequence searches/alignments with yeast or prokaryotic enzymes. None has been characterized in detail for intracellular function(s). Here, we describe a new human thioredoxin peroxidase, antioxidant enzyme AOE372, identified by virtue of its protein-protein interaction with the product of a proliferation associationgene, pag, which is also a thiol-specific antioxidant. In human cells, AOE372 defines a redox pathway that specifically regulates NF-κB activity via a modulation of IκB-α phosphorylation in the cytoplasm. We show that AOE372 activity is regulated through either homo- or heterodimerization with other thiol peroxidases, implicating subunit assortment as a mechanism for regulating antioxidant specificities. AOE372 function suggests thioredoxin peroxidase as an immediate regulator of H2O2-mediated activation of NF-κB. Reduction-oxidation (redox) plays a critical role in NF-κB activation. Diverse stimuli appear to utilize reactive oxygen species (e.g. hydrogen peroxide) as common effectors for activating NF-κB. Antioxidants govern intracellular redox status, and many such molecules can reduce H2O2. However, functionally, it does appear that different antioxidants are variously selective for redox regulation of certain transcription factors such as NF-κB. For NF-κB, thioredoxin has been described to be a more potent antioxidant than either glutathione orN-acetylcysteine. Thioredoxin peroxidase is the immediate enzyme that links reduction of H2O2 to thioredoxin. Several putative human thioredoxin peroxidases have been identified using recursive sequence searches/alignments with yeast or prokaryotic enzymes. None has been characterized in detail for intracellular function(s). Here, we describe a new human thioredoxin peroxidase, antioxidant enzyme AOE372, identified by virtue of its protein-protein interaction with the product of a proliferation associationgene, pag, which is also a thiol-specific antioxidant. In human cells, AOE372 defines a redox pathway that specifically regulates NF-κB activity via a modulation of IκB-α phosphorylation in the cytoplasm. We show that AOE372 activity is regulated through either homo- or heterodimerization with other thiol peroxidases, implicating subunit assortment as a mechanism for regulating antioxidant specificities. AOE372 function suggests thioredoxin peroxidase as an immediate regulator of H2O2-mediated activation of NF-κB. Living organisms produce reactive oxygen species such as H2O2 during physiological processes and in response to external stimuli such as UV radiation. To cope with potentially destructive reactive oxygen species, cells have evolved antioxidant defenses (reviewed in Ref. 1Scandalios J.G. Oxidative Stress and the Molecular Biology of Antioxidant Defenses. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1997Google Scholar). A delicate balance between oxidants and antioxidants is pivotally important for homeostasis. Several lines of evidence suggest that the regulation of intracellular redox, a process highly conserved in organisms ranging from bacteria to human, is a versatile control mechanism in signal transduction and gene expression (reviewed in Ref. 2Sen C.K. Packer L. FASEB J. 1996; 10: 709-720Crossref PubMed Scopus (1781) Google Scholar). In mammalian cells, intracellular redox status has been linked to cellular differentiation, immune response, growth control, tumor promotion, and apoptosis, as well as activation of viruses, notably HIV, 1The abbreviations used are: HIV, human immunodeficiency virus; TNF, tumor necrosis factor; TR, thioredoxin reductase; Trx, thioredoxin; Tpx, thioredoxin peroxidase; bp, base pair(s); PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; CAT, chloramphenicol acetyltransferase; SRE, serum response element; HTLV, human T-cell lymphotrophic virus; LTR, long terminal repeat; α-Pag, anti-Pag antibody; TPA, 12-O-tetradecanoylphorbol-13-acetate; PDC, paraquat dichloride. from latency (3Schreck R. Rieber P. Baeuerle P.A. EMBO J. 1991; 10: 2247-2258Crossref PubMed Scopus (3430) Google Scholar,4Kalebic T. Kinter A. Poli G. Anderson M.E. Meister A. Fauci A.S. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 986-990Crossref PubMed Scopus (319) Google Scholar). One redox-regulated protein is NF-κB. NF-κB is a member of the Rel family of transcription factors that exist ambiently in the cytoplasm via association with inhibitor protein, IκB (reviewed in Refs. 5Verma I.M. Stevenson J.K. Schwarz E.M. Antwerp D.V. Miyamoto S. Genes Dev. 1995; 9: 2723-2735Crossref PubMed Scopus (1665) Google Scholar and6Baeuerle P.A. Baltimore D. Cell. 1996; 87: 13-20Abstract Full Text Full Text PDF PubMed Scopus (2935) Google Scholar). A wide variety of stimuli including tumor necrosis factor-α (TNF-α), phorbol ester, bacterial lipopolysaccharide, and virus infection can activate NF-κB. Studies have implicated reactive oxygen species (i.e. H2O2) as one common signal transducer for these diverse stimuli (7Baeuerle P.A. Henkel T. Annu. Rev. Immunol. 1994; 12: 141-179Crossref PubMed Scopus (4602) Google Scholar, 8Anderson M.T. Staal F.J.T. Gilter C. Herzenberg L.A. Herzenberg L.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11527-11531Crossref PubMed Scopus (362) Google Scholar). How H2O2 might affect cytoplasmic and nuclear events that lead to the activated function of NF-κB is an important issue that remains incompletely elucidated. One pathway of NF-κB activation involves site-specific phosphorylation of IκB-α on serine residues 32 and 36. It has been suggested that serine phosphorylation targets IκB to the ubiquitin-proteasome pathway for degradation (9Palombella V.J. Rando O.J. Goldberg A.L. Maniatis T. Cell. 1994; 78: 773-785Abstract Full Text PDF PubMed Scopus (1922) Google Scholar, 10Traenckner E.B.-M. Pahl H.L. Henkel T. Schmidt K.N. Wilk S. Baeuerle P.A. EMBO J. 1995; 14: 2876-2883Crossref PubMed Scopus (934) Google Scholar, 11Chen Z.J. Parent L. Maniatis T. Cell. 1996; 84: 853-862Abstract Full Text Full Text PDF PubMed Scopus (871) Google Scholar). IκB inactivation, without proteolytic degradation, has also been reported to occur as a consequence of tyrosine phosphorylation on residue 42 (12Imbert V. Rupec R.A. Livolsi A. Pahl H.L. Traenckner E.B.-M. Mueller-Dieckmann C. Farahifar D. Rossi B. Auberger P. Baeuerle P.A. Peyron J.-F. Cell. 1996; 86: 787-798Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar). In both instances, phosphorylation results in an unmasking of the NF-κB nuclear localization signal facilitating nuclear entry of protein. Thus, for stimuli such as oxidative stress, which potently and rapidly modulates the nuclear activity of NF-κB, IκB-α may represent a critical activation target (5Verma I.M. Stevenson J.K. Schwarz E.M. Antwerp D.V. Miyamoto S. Genes Dev. 1995; 9: 2723-2735Crossref PubMed Scopus (1665) Google Scholar). Antioxidants govern intracellular redox status. Inside cells, glutathione, glutaredoxin, and thioredoxin (13Thomas J.A. Poland B. Honzatko R. Arch. Biochem. Biophys. 1995; 319: 1-9Crossref PubMed Scopus (365) Google Scholar) represent the major reducing agents. It is reasonable, although the evidence is not clear-cut, that different antioxidants should have preferential specificities for discrete redox pathways. A number of studies have suggested that thioredoxin is a specifically potent antioxidant for NF-κB activation (14Schenk H. Klein M. Erdbrugger W. Droge W. Schulze-Osthoff K. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1672-1676Crossref PubMed Scopus (644) Google Scholar, 15Okamoto T. Ogiwara H. Hayashi T. Mitsui A. Kawabe T. Yodoi J. Int. Immunol. 1992; 4: 811-819Crossref PubMed Scopus (134) Google Scholar, 16Hayashi T. Ueno Y. Okamoto T. J. Biol. Chem. 1993; 268: 11380-11388Abstract Full Text PDF PubMed Google Scholar). Thioredoxin reductase (TR), thioredoxin (Trx), and thioredoxin peroxidase (Tpx) are three linked components in a redox chain that couples peroxide reduction to NADPH oxidation (17Chae H.Z. Chung S.J. Rhee S.G. J. Biol. Chem. 1994; 269: 27670-27678Abstract Full Text PDF PubMed Google Scholar). In such a scheme, within cells, Tpx is the immediate enzyme that detoxifies hydrogen peroxide. Thioredoxin peroxidases are highly conserved in eukaryotes and prokaryotes (18Yamamoto T. Matsui Y. Natori S. Obinata M. Gene (Amst.). 1989; 80: 337-343Crossref PubMed Scopus (110) Google Scholar, 19Ishii T. Yamada M. Sato H. Matsue M. Taketani S. Nakayama K. Sugita Y. Bannai S. J. Biol. Chem. 1993; 268: 18633-18636Abstract Full Text PDF PubMed Google Scholar, 20Prosperi M.-T. Ferbus D. Karczinski I. Goubin G. J. Biol. Chem. 1993; 268: 11050-11056Abstract Full Text PDF PubMed Google Scholar, 21Chae H.Z. Uhm T.B. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7022-7026Crossref PubMed Scopus (281) Google Scholar, 22Lim Y.-S. Cha M.-K. Kim H.-K. Kim I.-H. Gene (Amst.). 1994; 140: 279-284Crossref PubMed Scopus (68) Google Scholar, 23Watabe S. Kohno H. Kouyama H. Hiroi T. Yago N. Nakazawa T. J. Biochem. 1994; 115: 648-654Crossref PubMed Scopus (99) Google Scholar, 24Iwahara S. Satoh H. Song D.-X. Webb J. Burlingame A.L. Nagae Y. Muller-Eberhard U. Biochemistry. 1995; PubMed Scopus (134) Google Scholar). of suggests a of of putative have been identified by sequence with yeast or bacteria enzymes. have suggested a new for mammalian that on and W. H. H. J. K. I. C. and S. G. in the or of human thioredoxin peroxidase One physiological is to and the intracellular of thiol-specific enzymes. the that redox might be regulated through protein-protein we for human cellular of a thiol-specific M.-T. Ferbus D. Karczinski I. Goubin G. J. Biol. Chem. 1993; 268: 11050-11056Abstract Full Text PDF PubMed Google Scholar, H.Z. K. G. G. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar). a yeast we a that a new enzyme AOE372 in a new as is a human thioredoxin AOE372 defines a redox pathway that to NF-κB activation. activity of AOE372 a role for human thioredoxin peroxidase in IκB-α phosphorylation in the cytoplasm. AOE372 from a human sequence from the by the of AOE372 on both by the using as the and with the of protein with a L. M. Biol. Google Scholar). on a of and the using the J. 1996; PubMed Google Scholar). in yeast to the with and with a human in for expression of and from and as described Scopus Google Scholar). and cells in a in of and and by through a by One of with of for of protein and the by three with and in gel anti-Pag a protein in with an of human AOE372, a of human and a human as the in gel by and using a by cells on number in with and with and for with in on and the with cells the for and by with on with by using from different species of and and to different and cells and with in of and and on for to of from and the for to the and the nuclear protein in from with an for the AOE372 protein as in protein through glutathione using and the of AOE372 in from with a or AOE372 AOE372 and by and on and by and by peroxidase and in (i.e. paraquat or as described (17Chae H.Z. Chung S.J. Rhee S.G. J. Biol. Chem. 1994; 269: 27670-27678Abstract Full Text PDF PubMed Google Scholar, K. Kim Rhee S.G. J. Biol. Chem. Full Text PDF PubMed Google Scholar, H.Z. Kim I.-H. Kim K. Rhee S.G. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar). and yeast have also been described Scopus Google Scholar). and gel as described Scopus Google Scholar). and used to produce a of cells and the as described Scopus Google Scholar, Cell. Biol. PubMed Scopus Google Scholar). on with a by and and have been described J.G. W. PubMed Scopus Google W. L. A. G. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). NF-κB SRE, and the on used to produce these are as NF-κB and and SRE, and and of protein and as reported J. 1993; PubMed Google Scholar). are highly conserved in many mammalian species including human, and (18Yamamoto T. Matsui Y. Natori S. Obinata M. Gene (Amst.). 1989; 80: 337-343Crossref PubMed Scopus (110) Google Scholar, 19Ishii T. Yamada M. Sato H. Matsue M. Taketani S. Nakayama K. Sugita Y. Bannai S. J. Biol. Chem. 1993; 268: 18633-18636Abstract Full Text PDF PubMed Google Scholar, 20Prosperi M.-T. Ferbus D. Karczinski I. Goubin G. J. Biol. Chem. 1993; 268: 11050-11056Abstract Full Text PDF PubMed Google Scholar, 21Chae H.Z. Uhm T.B. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7022-7026Crossref PubMed Scopus (281) Google Scholar, 22Lim Y.-S. Cha M.-K. Kim H.-K. Kim I.-H. Gene (Amst.). 1994; 140: 279-284Crossref PubMed Scopus (68) Google Scholar, 23Watabe S. Kohno H. Kouyama H. Hiroi T. Yago N. Nakazawa T. J. Biochem. 1994; 115: 648-654Crossref PubMed Scopus (99) Google Scholar, 24Iwahara S. Satoh H. Song D.-X. Webb J. Burlingame A.L. Nagae Y. Muller-Eberhard U. Biochemistry. 1995; PubMed Scopus (134) Google Scholar, H.Z. K. G. G. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar). of redox in of gene expression C.K. Packer L. FASEB J. 1996; 10: 709-720Crossref PubMed Scopus (1781) Google Scholar) to the of human chain to be we used the yeast S. Song 1989; PubMed Scopus Google Scholar) to protein-protein for the human thiol-specific M.-T. Ferbus D. Karczinski I. Goubin G. J. Biol. Chem. 1993; 268: 11050-11056Abstract Full Text PDF PubMed Google Scholar, H.Z. K. G. G. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar). in a we identified of the that protein can other of the A with the using of In the a sequence M. Cell. Full Text PDF PubMed Scopus Google Scholar) is the in and a is the of the sequence AOE372 is a protein of that has with a AOE372 has a its which is with a signal G. 14: PubMed Scopus Google Scholar) that has putative either and or and protein sequence of AOE372 has with including yeast thiol-specific antioxidant H.Z. Kim I.-H. Kim K. Rhee S.G. J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar) and bacterial reductase protein H.Z. K. G. G. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar). of AOE372 with human is in B. AOE372 the critical in human (i.e. the and have been implicated as important for of (17Chae H.Z. Chung S.J. Rhee S.G. J. Biol. Chem. 1994; 269: 27670-27678Abstract Full Text PDF PubMed Google Scholar, 21Chae H.Z. Uhm T.B. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7022-7026Crossref PubMed Scopus (281) Google Biochemistry. 1996; PubMed Scopus Google Scholar, H.Z. Rhee S.G. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the many residues in AOE372 and from for the other in sequence by H.Z. Uhm T.B. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7022-7026Crossref PubMed Scopus (281) Google Scholar, 24Iwahara S. Satoh H. Song D.-X. Webb J. Burlingame A.L. Nagae Y. Muller-Eberhard U. Biochemistry. 1995; PubMed Scopus (134) Google AOE372 from a new new suggested for the AOE372 is thiol-specific and represent for the and We to the antioxidant activity of We protein and it to AOE372 by reducing (e.g. and to be a discrete we the antioxidant of A activity is the of from by oxidation H.Z. K. G. G. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar, K. Kim Rhee S.G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). is by a thiol peroxidase activity (17Chae H.Z. Chung S.J. Rhee S.G. J. Biol. Chem. 1994; 269: 27670-27678Abstract Full Text PDF PubMed Google Scholar, H.Z. Rhee S.G. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). Here, thioredoxin as a hydrogen (17Chae H.Z. Chung S.J. Rhee S.G. J. Biol. Chem. 1994; 269: 27670-27678Abstract Full Text PDF PubMed Google Scholar, S.J. Kim Kim K. Biochem. Biophys. 1994; PubMed Scopus Google Scholar). We for and for thiol peroxidase In both AOE372 highly A and AOE372 the of thioredoxin and NADPH with and to a characterized thiol-specific antioxidant (17Chae H.Z. Chung S.J. Rhee S.G. J. Biol. Chem. 1994; 269: 27670-27678Abstract Full Text PDF PubMed Google Scholar). results AOE372 as a human thioredoxin of AOE372 in human and lines by AOE372 has an of AOE372 is in human lines including and However, the expression between different with and and and A and AOE372 not in To that be regulated the of we also for the expression of We that the AOE372 and expression with In the in and AOE372 more highly in such as Thus, exist expression for different To AOE372, we to a AOE372 for sequence of specifically with either protein or AOE372 protein and We used to the protein expression of AOE372 by in the protein and are with the the of a protein cells can important we human cells to the for AOE372 in the cytoplasm with either serum or with an of the of the cytoplasmic of AOE372 is with a for by of that AOE372 and with well characterized cytoplasmic and from protein, a well characterized nuclear I. J. Biol. 1992; PubMed Scopus Google Scholar). AOE372 identified as a in a yeast studies have suggested that thiol antioxidants be through H.Z. Uhm T.B. Rhee S.G. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7022-7026Crossref PubMed Scopus (281) Google Scholar). to human might homo- and and of protein-protein might the regulation of To we in yeast three human AOE372, and in We for between the three three AOE372 and in and heterodimerization of yeast in a new between AOE372 and using A and In with AOE372 and be and However, AOE372 and have of to from on in to for by with and and cells in with AOE372 or from these cells with a by to and with either or we that AOE372 with and that with AOE372 are with AOE372 and as in to to a cytoplasmic AOE372 has a function in intracellular in AOE372 signal transduction and gene To on AOE372 we its in cells might through redox, and by not a of AOE372 in We cells and for NF-κB activity by gel nuclear from cells with not activity by the of a of signal one in nuclear from cells different also from AOE372 cells are in NF-κB with in of AOE372 also and intracellular activation of NF-κB with with AOE372 described for thioredoxin K. H. Droge W. 1995; PubMed Scopus Google that the is the linked of the oxidants and antioxidants NF-κB activation is incompletely results thioredoxin peroxidase (i.e. as an in the pathway that regulates NF-κB. To the for we AOE372 the status of nuclear NF-κB and cytoplasmic We cells with and and IκB-α by In cells, we in nuclear and cytoplasmic IκB-α and For nuclear and nuclear AOE372 the of and to a of with the base one the of IκB-α are for one a of the species in the AOE372 be many one is that AOE372 the phosphorylation of activating and To for of AOE372 we cells using different agents. We that expression activated by tumor necrosis TPA, or AOE372 that expression and by AOE372 and of to AOE372 also cells with with the control of from different SRE, NF-κB, and that NF-κB and the by AOE372 of is by NF-κB G. Baltimore D. PubMed Scopus Google Scholar, C. T. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google Scholar, Baltimore D. J. PubMed Google Scholar). A important of AOE372 activity on NF-κB is to an on We for the of AOE372 on expression and the of infection on AOE372 In we show that AOE372 protein is in lines and that are with of of cells and AOE372 expression also in with are with a that infection by modulates the expression of of AOE372 in cells with the expression of as by either or are with a regulation of AOE372 and with the an on the through NF-κB. are of human thioredoxin activity of AOE372 on NF-κB to different of thioredoxin peroxidase might function we that the different human AOE372 and can AOE372 and protein-protein We of protein-protein interaction be To we intracellular using that are with In we that AOE372 a in the of yeast cells to from an paraquat In of a AOE372 and in to in between AOE372 and also in a with a different in We also cells and the expression of that AOE372 and in NF-κB activation to a than either AOE372 AOE372 results suggest that the activity of antioxidants can be regulated through either homo- or the evidence that intracellular subunit assortment between different of thioredoxin peroxidases and of are conserved in and of suggest that important in on recursive sequence searches/alignments using yeast and bacteria have suggested the of human (17Chae H.Z. Chung S.J. Rhee S.G. J. Biol. Chem. 1994; 269: 27670-27678Abstract Full Text PDF PubMed Google Scholar, H.Z. Rhee S.G. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, S.J. Kim Kim K. Biochem. Biophys. 1994; PubMed Scopus Google Scholar). Here, we the of a human We the evidence that the AOE372 of through cytoplasmic IκB-α to nuclear activity of NF-κB. One mammalian three and AOE372 the for a are more than one thioredoxin peroxidase can be by the that different of enzyme have in to which in the S. Kohno H. Kouyama H. Hiroi T. Yago N. Nakazawa T. J. Biochem. 1994; 115: 648-654Crossref PubMed Scopus (99) Google we that AOE372 and are to the cytoplasm with from T. Yamada M. Sato H. Matsue M. Taketani S. Nakayama K. Sugita Y. Bannai S. J. Biol. Chem. 1993; 268: 18633-18636Abstract Full Text PDF PubMed Google Scholar, 20Prosperi M.-T. Ferbus D. Karczinski I. Goubin G. J. Biol. Chem. 1993; 268: 11050-11056Abstract Full Text PDF PubMed Google Scholar, 23Watabe S. 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G. that AOE372 and not protein-protein cells suggests to have to the nuclear are that gene in the of from to are and incompletely and represent signal that activity by phosphorylation and and antioxidants represent a different of molecules that function through to redox can as the critical in many oxidants (e.g. hydrogen peroxide and that as molecules have been well S.J. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, K. Y. S.J. M. T. PubMed Scopus Google Scholar, A. T. J. Cell. 1996; 86: Full Text Full Text PDF PubMed Scopus Google Scholar). these oxidants are antioxidants such as glutathione, and J.G. Oxidative Stress and the Molecular Biology of Antioxidant Defenses. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1997Google Scholar). delicate cells between oxidants and antioxidants the activity for many transcription NF-κB is redox-regulated C.K. Packer L. FASEB J. 1996; 10: 709-720Crossref PubMed Scopus (1781) Google Scholar, F.J.T. Anderson M.T. 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A. 1994; 91: 11527-11531Crossref PubMed Scopus (362) Google Scholar). results show for the that an regulation of NF-κB involves the human thioredoxin peroxidase, that AOE372 has a on many different of NF-κB and suggests that it targets a common mechanism through which human thioredoxin peroxidase the nuclear NF-κB activity is We suggest that AOE372 modulates IκB-α phosphorylation in the cytoplasm and a redox results are with a an activity to glutathione peroxidase on IκB-α phosphorylation C. P. J. Biol. 1996; PubMed Scopus Google Scholar). However, it is that antioxidant the thioredoxin pathway to have the for NF-κB (14Schenk H. Klein M. Erdbrugger W. Droge W. Schulze-Osthoff K. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1672-1676Crossref PubMed Scopus (644) Google Scholar, 15Okamoto T. Ogiwara H. Hayashi T. Mitsui A. Kawabe T. Yodoi J. Int. Immunol. 1992; 4: 811-819Crossref PubMed Scopus (134) Google Scholar, 16Hayashi T. Ueno Y. Okamoto T. J. Biol. Chem. 1993; 268: 11380-11388Abstract Full Text PDF PubMed Google Scholar). IκB-α can be either on serine (9Palombella V.J. Rando O.J. Goldberg A.L. Maniatis T. Cell. 1994; 78: 773-785Abstract Full Text PDF PubMed Scopus (1922) Google Scholar, 10Traenckner E.B.-M. Pahl H.L. Henkel T. Schmidt K.N. Wilk S. Baeuerle P.A. EMBO J. 1995; 14: 2876-2883Crossref PubMed Scopus (934) Google Scholar, 11Chen Z.J. Parent L. Maniatis T. Cell. 1996; 84: 853-862Abstract Full Text Full Text PDF PubMed Scopus (871) Google Scholar) or on tyrosine 42 (12Imbert V. Rupec R.A. Livolsi A. Pahl H.L. Traenckner E.B.-M. Mueller-Dieckmann C. Farahifar D. Rossi B. Auberger P. Baeuerle P.A. Peyron J.-F. Cell. 1996; 86: 787-798Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar). an IκB has been described Song D.V. M. Cell. Full Text Full Text PDF PubMed Scopus Google J.A. M. M. PubMed Scopus Google Scholar). suggest that oxidants antioxidants might IκB of a AOE372, that IκB phosphorylation a to We and for critical of