The Human Cytomegalovirus UL26 Protein Antagonizes NF-κB Activation

Viral infection frequently triggers activation of host innate immune pathways that attempt to limit viral spread. The NF-kappa B pathway is a critical component that governs this response. We have found that the human cytomegalovirus (HCMV) U(L)26 protein antagonizes NF-kappa B activation. Upon infection, an HCMV strain lacking the U(L)26 gene (Delta U(L)26) induced the nuclear translocation of the NF-kappa B RelB subunit and activated expression and secretion of interleukin-6 (IL-6), an NF-kappa B target gene. The Delta U(L)26 mutant was also more sensitive to challenge with tumor necrosis factor alpha (TNF-alpha), a canonical NF-kappa B inducer. Further, expression of U(L)26 in the absence of other viral proteins blocked NF-kappa B activation induced by either TNF-alpha treatment or infection with Sendai virus (SeV). Our results indicate that U(L)26 expression is sufficient to block TNF-alpha-induced NF-kappa B nuclear translocation and I kappa B degradation. Last, U(L)26 blocks TNF-alpha-induced I kappa B-kinase (IKK) phosphorylation, a key step in NF-kappa B activation. Combined, our results indicate that U(L)26 is part of a viral program to antagonize innate immunity through modulation of NF-kappa B signaling. IMPORTANCE The NF-kappa B signaling pathway regulates innate immunity, an integral host process that limits viral pathogenesis. Viruses have evolved mechanisms to modulate NF-kappa B 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-kappa B pathway, which is important for HCMV infection. Our results indicate that the HCMV U(L)26 gene is a key modulator of NF-kappa B pathway activity. We find the U(L)26 gene is both necessary and sufficient to block NF-kappa B activation upon challenge with antiviral cytokines. Further, U(L)26 attenuates the phosphorylation and activation of a key NF-kappa B activating kinase complex, IKK. Our study provides new insight into how HCMV targets the NF-kappa B pathway. Given its importance to viral infection, the mechanisms through which viruses target the NF-kappa B pathway highlight areas of vulnerability that could be therapeutically targeted to attenuate viral replication.