Affiliation:
1. Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York, USA
2. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
Abstract
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.
IMPORTANCE
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.
Publisher
American Society for Microbiology
Subject
Virology,Insect Science,Immunology,Microbiology
Reference61 articles.
1. MocarskiESShenkTPassRF. 2007. Cytomegaloviruses, p 2701–2757. In KnipeDMHowleyPMGriffinDELambRAMartinMARoizmanBRStrausSE (ed), Fields virology, 5th ed. Lippincott Williams & Wilkins, New York, NY.
2. Congenital cytomegalovirus (CMV) epidemiology and awareness
3. Novel inhibitors of human CMV;Andrei G;Curr. Opin. Investig. Drugs,2008
4. Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: A quantitative assessment
5. Pathogenesis of human cytomegalovirus infection and cellular targets
Cited by
50 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献