Respiratory syncytial virus induces relA release from cytoplasmic 100-kDa NF-κB2 complexes via a novel retinoic acid-inducible gene-I·NF- κB-inducing kinase signaling pathway

Ping Liu, Kui Li, Roberto P. Garofalo, Allan R. Brasier

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)23169-23178
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number34
DOIs
StatePublished - Aug 22 2008

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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