Respiratory syncytial virus (RSV) is a primary cause of severe lower respiratory tract infection in children worldwide. RSV infects airway epithelial cells, where it activates inflammatory genes via the NF-κB pathway. NF-κB is controlled by two pathways, a canonical pathway that releases sequestered RelA complexes from the IκBα inhibitor, and a second, the noncanonical pathway, that releases RelB from the 100-kDa NF-κB2 complex. Recently we found that the retinoic acid-inducible gene I (RIG-I) is a major intracellular RSV sensor upstream of the canonical pathway. In this study, we surprisingly found that RIG-I silencing also inhibited p100 processing to 52-kDa NF-κB2 (“p52”), suggesting that RIG-I was functionally upstream of the noncanonical regulatory kinase complex composed of NIK·IKKα subunits. Co-immunoprecipitation experiments not only demonstrated that NIK associated with RIG-I and its downstream adaptor, mitochondrial antiviral signaling (MAVS), but also showed the association between IKKα and MAVS. To further understand the role of the NIK·IKKα pathway, we compared RSV-induced NF-κB activation using wild type, Ikkγ-/-, Nik-/-, and Ikkα-/--deficient MEF cells. Interestingly, we found that in canonical pathway-defective Ikkγ-/- cells, RSV induced RelA by liberation from p100 complexes. RSV was still able to activate IP10, Rantes, and Groβ gene expression in Ikkγ-/- cells, and this induction was inhibited by small interfering RNA-mediated RelA knockdown but not RelB silencing. These data suggest that part of the RelA activation in response to RSV infection was induced by a “cross-talk” pathway involving the noncanonical NIK·IKKα complex downstream of RIG-I·MAVS. This pathway may be a potential target for RSV treatment. Respiratory syncytial virus (RSV) is a primary cause of severe lower respiratory tract infection in children worldwide. RSV infects airway epithelial cells, where it activates inflammatory genes via the NF-κB pathway. NF-κB is controlled by two pathways, a canonical pathway that releases sequestered RelA complexes from the IκBα inhibitor, and a second, the noncanonical pathway, that releases RelB from the 100-kDa NF-κB2 complex. Recently we found that the retinoic acid-inducible gene I (RIG-I) is a major intracellular RSV sensor upstream of the canonical pathway. In this study, we surprisingly found that RIG-I silencing also inhibited p100 processing to 52-kDa NF-κB2 (“p52”), suggesting that RIG-I was functionally upstream of the noncanonical regulatory kinase complex composed of NIK·IKKα subunits. Co-immunoprecipitation experiments not only demonstrated that NIK associated with RIG-I and its downstream adaptor, mitochondrial antiviral signaling (MAVS), but also showed the association between IKKα and MAVS. To further understand the role of the NIK·IKKα pathway, we compared RSV-induced NF-κB activation using wild type, Ikkγ-/-, Nik-/-, and Ikkα-/--deficient MEF cells. Interestingly, we found that in canonical pathway-defective Ikkγ-/- cells, RSV induced RelA by liberation from p100 complexes. RSV was still able to activate IP10, Rantes, and Groβ gene expression in Ikkγ-/- cells, and this induction was inhibited by small interfering RNA-mediated RelA knockdown but not RelB silencing. These data suggest that part of the RelA activation in response to RSV infection was induced by a “cross-talk” pathway involving the noncanonical NIK·IKKα complex downstream of RIG-I·MAVS. This pathway may be a potential target for RSV treatment. In the United States, respiratory syncytial virus (RSV) 2The abbreviations used are:RSVrespiratory syncytial virusIKKIκB kinaseMAVSmitochondrial antiviral signalingNIKNFκB inducing kinaseRIG-Iretinoic acid-inducible gene IWTwild typeCARDcaspase recruitment domainTNFtumor necrosis factorLTβlymphotoxin βdsRNAdouble-stranded RNAsiRNAsmall interfering RNAMEFmouse embryonic fibroblastRTreverse transcriptasemAbmonoclonal antibodyCHXcycloheximideGFPgreen fluorescent proteinYFPyellow fluorescent proteinNEnuclear extractTRAFtumor necrosis factor receptor-associated factor. causes about 86,000 hospitalizations for severe lower respiratory tract infections (1Paramore L.C. Ciuryla V. Ciesla G. Liu L. Pharmacoeconomics. 2004; 22: 275-284Crossref PubMed Scopus (173) Google Scholar). Here, pathologic lesions such as bronchiolar epithelial necrosis, bronchiolar occlusion, parenchymal inflammation, and alveolar exudation are found (2Aherne W. Bird T. Court S.D. Gardner P.S. McQuillin J. J. Clin. Pathol. (Lond.). 1970; 23: 7-18Crossref PubMed Scopus (321) Google Scholar). These features, along with the finding that inhibition of mucosal NF-κB signaling in a mouse model of RSV disease blocks mononuclear infiltration and disease manifestations (3Haeberle H. Casola A. Gatalica Z. Petronella S. Dieterich H.-J. Ernst P.B. Brasier A.R. Garofalo R.P. J. Virol. 2004; 78: 2232-2241Crossref PubMed Scopus (54) Google Scholar), suggest that the inflammatory response mediates a lot of clinical disease manifestations. respiratory syncytial virus IκB kinase mitochondrial antiviral signaling NFκB inducing kinase retinoic acid-inducible gene I wild type caspase recruitment domain tumor necrosis factor lymphotoxin β double-stranded RNA small interfering RNA mouse embryonic fibroblast reverse transcriptase monoclonal antibody cycloheximide green fluorescent protein yellow fluorescent protein nuclear extract tumor necrosis factor receptor-associated factor. Previous studies have shown that RSV induces expression of 16 cytokines and chemokines (4Zhang Y. Luxon B.A. Casola A. Garofalo R.P. Jamaluddin M. Brasier A.R. J. Virol. 2001; 75: 9044-9058Crossref PubMed Scopus (197) Google Scholar), many of which are NF-κB dependent (5Jamaluddin M. Casola A. Garofalo R.P. Han Y. Elliott T. Ogra P.L. Brasier A.R. J. Virol. 1998; 72: 4849-4857Crossref PubMed Google Scholar, 6Liu T. Castro S. Brasier A.R. Jamaluddin M. Garofalo R.P. Casola A. J. Biol. Chem. 2004; 279: 2461-2469Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Five members of the NF-κB family have been reported, including three subunits with transactivating function, RelA, RelB, c-Rel, and two DNA binding subunits, NF-κB1 (p50) and NF-κB2 (p52) (7Siebenlist U. Franzoso G. Brown K. Annu. Rev. Cell Biol. 1994; 10: 405-455Crossref PubMed Scopus (2016) Google Scholar). The NF-κB molecules are sequestered in the cytoplasm by interacting with a group of inhibitory proteins including IκBα, IκBβ, IκBϵ, p100, and p105 (8Baldwin Jr., A.S. Annu. Rev. Immunol. 1996; 14: 649-683Crossref PubMed Scopus (5592) Google Scholar). Currently, it is understood that NF-κB activation can be controlled by two separate pathways, the canonical and noncanonical pathways, activated by distinct stimuli and under control of distinct IκB kinase (IKK) complexes. The canonical NF-κB pathway is induced by the monokines TNF and interleukin-1, stimulating the IKK complex composed of the catalytic kinases, IKK-α and-β and the regulatory subunit, IKKγ (9Zandi E. Karin M. Mol. Cell. Biol. 1999; 19: 4547-4551Crossref PubMed Scopus (307) Google Scholar). Activated IKK, in turn, induces the phosphorylation-coupled degradation of IκBα, liberating sequestered cytoplasmic RelA allowing RelA to translocate into the nucleus and initiates gene transcription (10Ghosh S. Baltimore D. Nature. 1990; 344: 678-682Crossref PubMed Scopus (909) Google Scholar). The non-canonical NF-κB pathway is induced by lymphotoxin β (LTβ), the TNF superfamily member, LIGHT, or other lymphokines (11Dejardin E. Droin N.M. Delhase M. Haas E. Cao Y. Makris C. Li Z.W. Karin M. Ware C.F. Green D.R. Immunity. 2002; 17: 525-535Abstract Full Text Full Text PDF PubMed Scopus (781) Google Scholar, 12Xiao G. Harhaj E.W. Sun S.C. Mol. Cell. 2001; 7: 401-409Abstract Full Text Full Text PDF PubMed Scopus (696) Google Scholar, 13Xiao G. Fong A. Sun S.C. J. Biol. Chem. 2004; 279: 30099-30105Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar, 14Kanno T. Franzoso G. Siebenlist U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 12634-12638Crossref PubMed Scopus (55) Google Scholar). This pathway stimulates a complex of NIK and IKKα, resulting in the phosphorylation-coupled proteolysis of 100-kDa NF-κB2 (“p100”) to form the activated 52-kDa NF-κB2 (“p52”)-RelB complex. Although we found that RSV was able to activate NIK kinase activity and p52 formation (15Choudhary S. Boldogh S. Garofalo R.P. Jamaluddin M. Brasier A.R. J. Virol. 2005; 79: PubMed Scopus Google Scholar), the RSV activates the NIK·IKKα complex is we found that retinoic acid-inducible gene I a RNA was the intracellular sensor for RSV infection and upstream of the canonical NF-κB pathway Jamaluddin M. Li K. Garofalo R.P. Casola A. Brasier A.R. J. Virol. PubMed Scopus Google Scholar). RIG-I is a of signaling for of the RNA H. S. M. M. S. K. T. K. T. S. Immunity. 2005; 23: Full Text Full Text PDF PubMed Scopus Google Scholar, H. S. M. M. K. S. A. T. K. T. C. Y. T. S. Nature. PubMed Scopus Google Scholar). RIG-I is upstream of the mitochondrial antiviral signaling also as caspase recruitment domain inducing or signaling Sun L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, T. K. S. C. H. H. S. Immunol. 2005; PubMed Scopus Google Scholar, H. T. H. S. K. C. M. S. S. J. PubMed Scopus Google Scholar, E. J. K. D. M. Nature. 2005; PubMed Scopus Google Scholar, M. V. G. S. H. J. T. A. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Activated RIG-I to a this is for downstream RIG-I signaling and the mitochondrial Sun L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In this study, we that RIG-I silencing and p52 that NIK with the complex via the RIG-I domain and the of we found RSV induced RelA activation in Ikkγ-/- mouse embryonic a canonical NF-κB pathway. In we demonstrated that the NIK·IKKα complex induced RelA from cytoplasmic p100 complexes. RIG-I RelA activation by two distinct downstream signaling by canonical pathway activation and the involving a pathway dependent complex formation with NIK·IKKα activation RelA from p100 of this pathway may have in the inflammatory response to RSV the Cell type epithelial in with and in a type, L. L. H. 2001; PubMed Scopus Google Scholar), M. E. Karin M. Nature. PubMed Scopus Google Scholar), and Ikkγ-/- S. G. C. A. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google in with and in with and and RSV was in and as Google Scholar). The of RSV was from to by a and into and RSV a of infection of for the as in the and a of of NIK by and as into the The of the are shown in NIK expression was as a in RIG-I and its under the control of a response in a as Jamaluddin M. Li K. Garofalo R.P. Casola A. Brasier A.R. J. Virol. PubMed Scopus Google Scholar). and by and into of the the used are in was into using upstream and downstream for of in a for of in a RIG-I mouse mouse and control from The RIG-I and control into using a to the The control and the RelA and RelB into MEF using reverse to the RSV the The silencing of was using reverse for RIG-I as as for RelB and and RNA was using of RNA was using in a of was and was in a of Green and of and reverse into and with The for and to of and in was to a of gene expression was Jamaluddin M. Li K. Garofalo R.P. Casola A. Brasier A.R. J. Virol. PubMed Scopus Google for in a of of in of and of double-stranded NF-κB binding in a of as Y. Luxon B.A. Garofalo R.P. Casola A. M. Brasier A.R. J. Virol. 2002; PubMed Scopus Google Scholar). and to for Co-immunoprecipitation and using and of and with protein for and was for with primary complexes by of protein and for three with and complexes by and to a by in in and with the primary in the and with or the three with and by of primary and antibody the experiments the primary the was not to the primary and the primary antibody was with in of and with of to and for treatment. RSV-induced p52 and we have that RSV infection activated the noncanonical pathway. To we with the Liu Mol. Cell. Biol. 2005; PubMed Scopus Google Scholar), a noncanonical pathway and compared p52 formation with that induced by RSV infection and induced p52 formation which for In we p100 expression was a of p100 downstream of the NF-κB pathway Brasier A.R. PubMed Scopus Google Scholar). RSV infection induced p52 formation RSV and for In to the response to LIGHT, the p100 was induced the and not This is to the activation of the noncanonical pathway in RSV infection (15Choudhary S. Boldogh S. Garofalo R.P. Jamaluddin M. Brasier A.R. J. Virol. 2005; 79: PubMed Scopus Google Scholar). Previous from shown that RSV-induced NF-κB activation is dependent with RSV or to NF-κB binding to (5Jamaluddin M. Casola A. Garofalo R.P. Han Y. Elliott T. Ogra P.L. Brasier A.R. J. Virol. 1998; 72: 4849-4857Crossref PubMed Google Scholar). To RSV is for p100 to or from cells. Although RSV induced p52 RSV from p52 formation Interestingly, p52 formation been shown to be via a where p100 was the target for processing to p52 D. M. M. C. PubMed Scopus Google Scholar). In this study, it was shown that cycloheximide the formation of p100 and To RSV induced p52 formation also via a RSV infection was in the of that inhibited the formation of the p100 and p52 formation was inhibited These data that RSV was for p52 and that p100 was the primary of p52 RIG-I is the major cytoplasmic sensor of RSV infection upstream of the canonical pathway, but the pathway noncanonical activation is Jamaluddin M. Li K. Garofalo R.P. Casola A. Brasier A.R. J. Virol. PubMed Scopus Google Scholar). RIG-I RSV-induced p52 this we RIG-I expression using In with control cells, where RIG-I was not in and its expression was RSV of RIG-I was in with the and RSV-induced p52 was in To the NIK and IKKα in noncanonical pathway p52 formation was in wild type and Here, p52 formation was in and Ikkγ-/- RSV but was in and These data that RSV-induced p52 formation was RIG-I involving the NIK and IKKα RIG-I and with NIK and further the between RIG-I and and the experiments and into cells. The RIG-I the RIG-I the two and the RIG-I part the domain NIK was using the and RIG-I association was by using from These that NIK to RIG-I and but not suggesting that the two of RIG-I are for complex To this the reverse was using the to RIG-I and NIK association using in the The was in this from the downstream RIG-I with Co-immunoprecipitation experiments using and NIK and of MAVS. this of and used including wild type (MAVS), in its domain in its domain and its and NIK was using and association by in The was to using and NIK using in from experiments the only the associated with To that this was not the of we to the this with or with The of NIK was in the complexes by NIK was only in the These data that the proteins a complex in To which NIK for complex experiments using NIK of expression and domain These with and complexes using that the of NIK and with but the and not This that the of NIK was for with MAVS. of the role of IKKα in the noncanonical pathway, and its for RSV-induced p52 formation in the association of IKKα and was also IKKα was with or of MAVS. The complex was using and IKKα association using in the that only IKKα To this IKKα and into cells. of IKKα and by are shown in The two and The of two molecules is demonstrated by the yellow in the In the only the IKKα is the In the is only and the is the The other and the of green to a mitochondrial is data that IKKα is to with the RSV RelA in Ikkγ-/- further understand the of the NIK·IKKα complex in RSV-induced we Ikkγ-/-, Nik-/-, and with RSV and nuclear for canonical NF-κB DNA binding activity using a Y. Luxon B.A. Garofalo R.P. Casola A. M. Brasier A.R. J. Virol. 2002; PubMed Scopus Google Scholar). In cells, RSV induces the of a DNA binding complex and in Ikkγ-/- cells, RelA DNA binding activity was not RSV RelA binding was induced infection from complexes in and To which of the NF-κB family this DNA protein from Ikkγ-/- with or and a was the with RelA a to that RelA is in the DNA binding complex in Ikkγ-/- cells. To further the complexes in Ikkγ-/-, Nik-/-, and to for RelA, RelB, and complexes three the members of the DNA binding complex RelA and as by the of to the RSV complex and form a in To RelA from Ikkγ-/-, Nik-/-, and for in RelA by Here, RSV infection induced the nuclear RelA in RSV infection the nuclear of RelA in Ikkγ-/- to that RSV induces RelA of the canonical pathway. To that RelA was a NF-κB gene domain E. A. A. J. J. J. Virol. 1994; PubMed Google was into Ikkγ-/- and to the or of in activity was in the further the of RelA in RSV-induced gene expression in Ikkγ-/- cells. To its function, we RelA or RelB by The of knockdown was using to RelA and RelB Here, a inhibition of RelA or RelB expression was by the In the or cells, the RSV-induced expression of IP10, Rantes, and Groβ by In with control Rantes, and Groβ about and of induction was in the with RelB, the expression of the three genes RelA was in These data the of signaling pathway that activates RelA is for activity of target of RelA from p100 canonical pathway from Nik-/-, and Ikkγ-/- and was using RSV-induced IκBα proteolysis was in Nik-/-, and IκBα degradation was in Ikkγ-/- This data not only demonstrated that RSV was able to activate the canonical NF-κB pathway, but also that RSV-induced RelA activation in Ikkγ-/- was of IκBα Previous studies have that p100 a with RelA and as to RelA in the cytoplasm T. Franzoso G. Siebenlist U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 12634-12638Crossref PubMed Scopus (55) Google Scholar, S.C. C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar). the RelA from p100 are not showed that p52 formation was we RSV induced RelA from complexes in and Ikkγ-/- To the was Here, p100 was in cytoplasmic from and Ikkγ-/- and was using and In p100 was associated with RSV RelA was the in the Ikkγ-/- These data that RSV-induced RelA in by proteolysis of These data that RSV-induced activation of the noncanonical pathway in RelA To a in response to a of the noncanonical pathway, we induced RelA In this with or for or for RelA and RelB by that induced RelA and RelB of only induced RelA RSV in Ikkγ-/-, but in and the role of the canonical and in Nik-/-, and Ikkγ-/- RSV of proteins was using using and protein Although the of protein expression was in Nik-/-, and a in protein expression was in the Ikkγ-/- In in to the and in Nik-/-, and a in and was in the Ikkγ-/- These data that IKKγ mediates signaling but the this finding that inhibition of the signaling pathway may inflammatory but not RIG-I is a major intracellular sensor that RSV infection and activates the downstream NF-κB and by with the Jamaluddin M. Li K. Garofalo R.P. Casola A. Brasier A.R. J. Virol. PubMed Scopus Google Scholar). In this study, we the for RSV induces NF-κB it is that NF-κB is by two separate the canonical and noncanonical The canonical NF-κB pathway is and RelA from cytoplasmic IκBα complexes. the noncanonical pathway is and and in RelB from cytoplasmic p100 complexes. Although stimuli activate the canonical pathway or the noncanonical pathway RSV activates (5Jamaluddin M. Casola A. Garofalo R.P. Han Y. Elliott T. Ogra P.L. Brasier A.R. J. Virol. 1998; 72: 4849-4857Crossref PubMed Google Scholar, S. Boldogh S. Garofalo R.P. Jamaluddin M. Brasier A.R. J. Virol. 2005; 79: PubMed Scopus Google Scholar, M. Jamaluddin M. Casola A. Ogra P.L. Brasier A.R. J. Virol. 1996; PubMed Google Scholar). The by which RIG-I to the canonical pathway is but the RSV activates the noncanonical via the NIK·IKKα kinase complex is we the that RIG-I activates RelA from p100 complexes by the noncanonical NIK·IKKα subunits in Ikkγ-/- cells. The that noncanonical pathway activation is dependent RSV that in of and that this pathway is inhibited RIG-I knockdown that RIG-I activation is and upstream of the noncanonical pathway. These data the of “cross-talk” pathway that mediates of the RelA To this data is the to that NIK with the signaling complex. NIK is a kinase of the kinase family to with the TNF receptor-associated and the and factor and the IKKα kinase D. Nature. PubMed Scopus Google Scholar, G. Sun S.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. G. E. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, G. M. Harhaj E.W. Sun S.C. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). association NIK to with activated in the TNF that NIK as a binding IKKα, that IKKα to complex with p100 to and p52 formation (11Dejardin E. Droin N.M. Delhase M. Haas E. Cao Y. Makris C. Li Z.W. Karin M. Ware C.F. Green D.R. Immunity. 2002; 17: 525-535Abstract Full Text Full Text PDF PubMed Scopus (781) Google Scholar). These have been to the NIK The of NIK and G. M. Harhaj E.W. Sun S.C. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), the is to with of and IKKα of D. Nature. PubMed Scopus Google Scholar, G. Sun S.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. G. E. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). experiments that the NIK is also for of the of protein it is that a complex is between IKKα, and to a signaling complex. be to which proteins is for activated RIG-I not have activity and as a for signaling complex In this the complex been shown to be to the of via a domain the protein Sun L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Previous shown that in the of are to activate the canonical or the signaling in response to or infections Sun L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, T. K. S. C. H. H. S. Immunol. 2005; PubMed Scopus Google Scholar, H. T. H. S. K. C. M. S. S. J. PubMed Scopus Google Scholar, E. J. K. D. M. Nature. 2005; PubMed Scopus Google Scholar, M. V. G. S. H. J. T. A. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, in the of mitochondrial is to with RIG-I or its data that mitochondrial is for NIK NIK to to the which to the cytoplasm and Sun L. Cell. 2005; Full Text Full Text PDF PubMed Scopus Google finding is for the The for a mitochondrial for signaling is data is the to that NIK association with the complex mediates a signaling pathway, a pathway in RelA from p100 complexes. RelA is sequestered in the cytoplasm association with including IκBα, IκBβ, IκBϵ, and p100, which to as for NF-κB T. Franzoso G. Siebenlist U. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 12634-12638Crossref PubMed Scopus (55) Google Scholar, S.C. C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar, C. Karin M. 7: PubMed Scopus Google Scholar, M. A. C. Google Scholar, Jr., A.S. Mol. Cell Biol. PubMed Google Scholar). The canonical pathway RelA liberation from and complexes. In this study, we that RSV induces the degradation of IκBα in Nik-/-, and but not in Ikkγ-/- This that RSV-induced IκBα proteolysis is IKKγ RSV is still able to activate RelA and activation in Ikkγ-/- that and T. L. Sun M. J. Immunol. PubMed Scopus Google also a of gene expression in Ikkγ-/- with Although the of the was not that gene activity was inhibited by IκBα, suggesting RelA T. L. Sun M. J. Immunol. PubMed Scopus Google Scholar). a for the activation of RelA via a complex with and the noncanonical model of the pathway is shown in RelA as a of p100 processing to be under a separate control the canonical pathway. this pathway was as downstream of a TNF superfamily that also induces IκBα RelA from cytoplasmic p100 complexes S. H. V. E. Ware C.F. G. A. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). that also induces RelA and signaling are of we that signaling can the cytoplasmic complexes including activated by TNF superfamily of and cytoplasmic we that the of this pathway was by the of RSV to RelA activation in Ikkγ-/- this pathway is activated in wild type and epithelial cells. In cytoplasmic RelA is associated with p100, and that p100 processing is induced by p52 in response to RSV that the activation of the noncanonical NIK·IKKα complexes induces the of RelA as as the noncanonical (p52) complex The NF-κB DNA binding complex is composed of a of a transactivating with a DNA binding we understand the canonical is the DNA binding complex in in binding by studies and In this RelA is for of the and M. Casola A. Garofalo R.P. Han Y. Elliott T. Ogra P.L. Brasier A.R. J. Virol. 1998; 72: 4849-4857Crossref PubMed Google and Y. Luxon B.A. Garofalo R.P. Casola A. M. Brasier A.R. J. Virol. 2002; PubMed Scopus Google Scholar). RSV-induced RelA is from two separate cytoplasmic and Although p100 processing releases RelA and RelB in Ikkγ-/- we by knockdown that RelA, and not RelB, is the major of RSV-induced Rantes, and Groβ that p52 formation is to the protein is to of D. M. M. C. PubMed Scopus Google Scholar), demonstrated that p52 processing is to p100 in response to and to that RNA virus infection also activates RelA from sequestered p100 via a The role of the noncanonical (p52) complex in epithelial is Previous using knockdown of p52 that p52 complexes only to a expression (15Choudhary S. Boldogh S. Garofalo R.P. Jamaluddin M. Brasier A.R. J. Virol. 2005; 79: PubMed Scopus Google Scholar). In the complex activates a distinct of including and (11Dejardin E. Droin N.M. Delhase M. Haas E. Cao Y. Makris C. Li Z.W. Karin M. Ware C.F. Green D.R. Immunity. 2002; 17: 525-535Abstract Full Text Full Text PDF PubMed Scopus (781) Google Scholar). genes are not by epithelial the role of the noncanonical pathway is the only data is that the complex the of canonical pathway activation in RSV infection (15Choudhary S. Boldogh S. Garofalo R.P. Jamaluddin M. Brasier A.R. J. Virol. 2005; 79: PubMed Scopus Google Scholar). group showed that inhibition of the canonical NF-κB pathway using a that binding the inflammatory in RSV (3Haeberle H. Casola A. Gatalica Z. Petronella S. Dieterich H.-J. Ernst P.B. Brasier A.R. Garofalo R.P. J. Virol. 2004; 78: 2232-2241Crossref PubMed Scopus (54) Google Scholar). IKKγ was also shown to activation of the pathway downstream of the inhibition of IKKγ was for T. L. Sun M. J. Immunol. PubMed Scopus Google Scholar). that IKKγ the inflammatory response as as the In of the pathway, we have the finding that a of RSV-induced inflammatory is by the noncanonical NIK·IKKα complex. NIK and IKKα signaling not in RSV These of the pathway NIK and IKKα potential for by RSV the of from of and for the of cells.
No takes yet. Share an insight, caveat, or question.
Liu et al. (2008) studied this question.
Synapse has enriched 4 closely related papers on similar clinical questions. Consider them for comparative context: