title: The human cytomegalovirus UL26 protein antagonizes NF-κB activation.
abstract: Viral infection frequently triggers activation of host innate immune pathways that attempt to limit viral spread. The NF-κB pathway is a critical component that governs this response. We have found that the human cytomegalovirus (HCMV) U(L)26 protein antagonizes NF-κB activation. Upon infection, an HCMV strain lacking the U(L)26 gene (ΔU(L)26) induced the nuclear translocation of the NF-κB RelB subunit and activated expression and secretion of interleukin-6 (IL-6), an NF-κB target gene. The ΔU(L)26 mutant was also more sensitive to challenge with tumor necrosis factor alpha (TNF-α), a canonical NF-κB inducer. Further, expression of U(L)26 in the absence of other viral proteins blocked NF-κB activation induced by either TNF-α treatment or infection with Sendai virus (SeV). Our results indicate that U(L)26 expression is sufficient to block TNF-α-induced NF-κB nuclear translocation and IκB degradation. Last, U(L)26 blocks TNF-α-induced IκB-kinase (IKK) phosphorylation, a key step in NF-κB activation. Combined, our results indicate that U(L)26 is part of a viral program to antagonize innate immunity through modulation of NF-κB signaling.
  
  
  OBJECTIVE
  The NF-κB signaling pathway regulates innate immunity, an integral host process that limits viral pathogenesis. Viruses have evolved mechanisms to modulate NF-κB signaling to ensure their replication. HCMV is a major cause of birth defects and disease in immunosuppressed populations. HCMV is known to actively target the NF-κB pathway, which is important for HCMV infection. Our results indicate that the HCMV U(L)26 gene is a key modulator of NF-κB pathway activity. We find the U(L)26 gene is both necessary and sufficient to block NF-κB activation upon challenge with antiviral cytokines. Further, U(L)26 attenuates the phosphorylation and activation of a key NF-κB activating kinase complex, IKK. Our study provides new insight into how HCMV targets the NF-κB pathway. Given its importance to viral infection, the mechanisms through which viruses target the NF-κB pathway highlight areas of vulnerability that could be therapeutically targeted to attenuate viral replication.
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Mathers
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Xenia
authors.initials: X
authors.lastname: Schafer
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Sobrido
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA josh.munger@rochester.edu.
authors.forename: Joshua
authors.initials: J
authors.lastname: Munger
mesh_terms: D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007108:Immune Tolerance; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins