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Articles by Allan R. Brasier
Total Records ( 2 ) for Allan R. Brasier
  Ping Liu , Kui Li , Roberto P. Garofalo and Allan R. Brasier
  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.
  Tieying Hou , Sutapa Ray , Chang Lee and Allan R. Brasier
  Signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor mainly activated by the interleukin-6 cytokine family. Previous studies have shown that activated STAT3 recruits p300, a coactivator whose intrinsic histone acetyltransferase activity is essential for transcription. Here we investigated the function of the STAT3 NH2-terminal domain and how its interaction with p300 regulates STAT3 signal transduction. In STAT3-/- mouse embryonic fibroblasts, a stably expressed NH2 terminus-deficient STAT3 mutant (STAT3-ΔN) was unable to efficiently induce either STAT3-mediated reporter activity or endogenous mRNA expression. Chromatin immunoprecipitation assays were performed to determine whether the NH2-terminal domain regulates p300 recruitment or stabilizes enhanceosome assembly. Despite equivalent levels of STAT3 binding, cells expressing the STAT3-ΔN mutant were unable to recruit p300 and RNA polymerase II to the native socs3 promoter as efficiently as those expressing STAT3-full length. We previously reported that the STAT3 NH2-terminal domain is acetylated by p300 at Lys-49 and Lys-87. By introducing K49R/K87R mutations, here we found that the acetylation status of the STAT3 NH2-terminal domain regulates its interaction with p300. In addition, the STAT3 NH2-terminal binding site maps to the p300 bromodomain, a region spanning from amino acids 995 to 1255. Finally a p300 mutant lacking the bromodomain (p300-ΔB) exhibited a weaker binding to STAT3, and the enhanceosome formation on the socs3 promoter was inhibited when p300-ΔB was overexpressed. Taken together, our data suggest that the STAT3 NH2-terminal domain plays an important role in the interleukin-6 signaling pathway by interacting with the p300 bromodomain, thereby stabilizing enhanceosome assembly.
 
 
 
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