Respiratory syncytial virus induces RelA release from cytoplasmic 100-kDa NF-kappa B2 complexes via a novel retinoic acid-inducible gene-I{middle dot}NF- kappa B-inducing kinase signaling pathway.
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-kappaB pathway. NF-kappaB is controlled by two pathways, a canonical pathway that releases sequestered RelA complexes from the IkappaBalpha inhibitor, and a second, the noncanonical pathway, that releases RelB from the 100-kDa NF-kappaB2 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-kappaB2 ("p52"), suggesting that RIG-I was functionally upstream of the noncanonical regulatory kinase complex composed of NIK.IKKalpha 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 IKKalpha and MAVS. To further understand the role of the NIK.IKKalpha pathway, we compared RSV-induced NF-kappaB activation using wild type, Ikkgamma(-/-), Nik(-/-), and Ikkalpha(-/-)-deficient MEF cells. Interestingly, we found that in canonical pathway-defective Ikkgamma(-/-) cells, RSV induced RelA by liberation from p100 complexes. RSV was still able to activate IP10, Rantes, and Grobeta gene expression in Ikkgamma(-/-) 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.IKKalpha complex downstream of RIG-I.MAVS. This pathway may be a potential target for RSV treatment.
Department of Medicine, University of Texas Medical Branch, Galveston, TX 77555-1060, USA.
Ping
P
Liu
Kui
K
Li
Roberto P
RP
Garofalo
Allan R
AR
Brasier
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic; D012136:Respiratory Syncytial Viruses / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D011971:Receptors, Immunologic; D051996:Transcription Factor RelA; D000097782:NF-kappaB-Inducing Kinase; C505371:MAVS protein, human; C498206:NFKB2 protein, human; C498207:Nfkb2 protein, mouse; C498143:RELA protein, human; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; C512612:MAVS protein, mouse