{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T21:27:36Z","timestamp":1789939656680,"version":"4.0.1"},"reference-count":61,"publisher":"American Society for Microbiology","issue":"24","license":[{"start":{"date-parts":[[2014,12,15]],"date-time":"2014-12-15T00:00:00Z","timestamp":1418601600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2014,12,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Viral infection frequently triggers activation of host innate immune pathways that attempt to limit viral spread. The NF-\u03baB pathway is a critical component that governs this response. We have found that the human cytomegalovirus (HCMV) U<jats:sub>L<\/jats:sub>26 protein antagonizes NF-\u03baB activation. Upon infection, an HCMV strain lacking the U<jats:sub>L<\/jats:sub>26 gene (\u0394U<jats:sub>L<\/jats:sub>26) induced the nuclear translocation of the NF-\u03baB RelB subunit and activated expression and secretion of interleukin-6 (IL-6), an NF-\u03baB target gene. The \u0394U<jats:sub>L<\/jats:sub>26 mutant was also more sensitive to challenge with tumor necrosis factor alpha (TNF-\u03b1), a canonical NF-\u03baB inducer. Further, expression of U<jats:sub>L<\/jats:sub>26 in the absence of other viral proteins blocked NF-\u03baB activation induced by either TNF-\u03b1 treatment or infection with Sendai virus (SeV). Our results indicate that U<jats:sub>L<\/jats:sub>26 expression is sufficient to block TNF-\u03b1-induced NF-\u03baB nuclear translocation and I\u03baB degradation. Last, U<jats:sub>L<\/jats:sub>26 blocks TNF-\u03b1-induced I\u03baB-kinase (IKK) phosphorylation, a key step in NF-\u03baB activation. Combined, our results indicate that U<jats:sub>L<\/jats:sub>26 is part of a viral program to antagonize innate immunity through modulation of NF-\u03baB signaling.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The NF-\u03baB signaling pathway regulates innate immunity, an integral host process that limits viral pathogenesis. Viruses have evolved mechanisms to modulate NF-\u03baB 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-\u03baB pathway, which is important for HCMV infection. Our results indicate that the HCMV U<jats:sub>L<\/jats:sub>26 gene is a key modulator of NF-\u03baB pathway activity. We find the U<jats:sub>L<\/jats:sub>26 gene is both necessary and sufficient to block NF-\u03baB activation upon challenge with antiviral cytokines. Further, U<jats:sub>L<\/jats:sub>26 attenuates the phosphorylation and activation of a key NF-\u03baB activating kinase complex, IKK. Our study provides new insight into how HCMV targets the NF-\u03baB pathway. Given its importance to viral infection, the mechanisms through which viruses target the NF-\u03baB pathway highlight areas of vulnerability that could be therapeutically targeted to attenuate viral replication.<\/jats:p>","DOI":"10.1128\/jvi.02552-14","type":"journal-article","created":{"date-parts":[[2014,10,2]],"date-time":"2014-10-02T08:30:33Z","timestamp":1412238633000},"page":"14289-14300","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":66,"title":["The Human Cytomegalovirus U<sub>L<\/sub>26 Protein Antagonizes NF-\u03baB Activation"],"prefix":"10.1128","volume":"88","author":[{"given":"Chun","family":"Mathers","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xenia","family":"Schafer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Mart\u00ednez-Sobrido","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Munger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"2701","volume-title":"Fields virology","author":"Mocarski ES","year":"2007","unstructured":"MocarskiESShenkTPassRF. 2007. 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