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UL26 Attenuates IKK?-Mediated Induction of Interferon-Stimulated Gene (ISG) Expression and Enhanced Protein ISGylation during Human Cytomegalovirus Infection.


ABSTRACT: Viruses must negotiate cellular antiviral responses in order to replicate. Human cytomegalovirus (HCMV) is a prevalent betaherpesvirus that encodes a number of viral gene products that modulate cellular antiviral signaling. The HCMV UL26 gene has previously been found to attenuate cytokine-activated NF-?B signaling, yet the role that UL26 plays in modulating the host cell's global transcriptional response to infection is not clear. Here, we find that infection with a UL26 deletion virus (?UL26) induces a proinflammatory transcriptional environment that includes substantial increases in the expression of cytokine signaling genes relative to wild-type HCMV. These increases include NF-?B-regulated genes as well as interferon-stimulated genes (ISGs), such as ISG15 and bone marrow stromal cell antigen 2 (BST2). The ?UL26 mutant-mediated induction of ISG15 expression was found to drive increases in global protein ISGylation during ?UL26 mutant infection. However, short hairpin RNA (shRNA) and CRISPR-mediated targeting of ISG15 indicated that its induction does not restrict HCMV infection. In contrast, shRNA-mediated targeting of BST2 demonstrated that BST2 restricts HCMV cell-to-cell spread. In addition, the increased expression of both of these ISGs and the global enhancement in protein ISGylation were found to be dependent on the activity of the canonical inhibitor of NF-?B kinase beta (IKK?). Both CRISPR-based and pharmacologically mediated inhibition of IKK? blocked the induction of ISG15 and BST2. These results suggest significant cross-talk between the NF-?B and interferon signaling pathways and highlight the importance of IKK signaling and the HCMV UL26 protein in shaping the antiviral response to HCMV.IMPORTANCE Modulation of cellular antiviral signaling is a key determinant of viral pathogenesis. Human cytomegalovirus (HCMV) is a significant source of morbidity in neonates and the immunosuppressed that contains many genes that modulate antiviral signaling, yet how these genes contribute to shaping the host cell's transcriptional response to infection is largely unclear. Our results indicate that the HCMV UL26 protein is critical in preventing the establishment of a broad cellular proinflammatory transcriptional environment. Further, we find that the host gene IKK? is an essential determinant governing the host cell's antiviral transcriptional response. Given their importance to viral pathogenesis, continuing to elucidate the functional interactions between viruses and the cellular innate immune response could enable the development of therapeutic strategies to limit viral infection.

PROVIDER: S-EPMC6854504 | BioStudies |

REPOSITORIES: biostudies

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