Abstract:
:Accumulation of the interferon-stimulated gene 15 (ISG15) protein product, which is reversibly conjugated to numerous polypeptide targets, impacts the proteome and physiology of uninfected and infected cells. While many viruses, including human cytomegalovirus (HCMV), blunt host antiviral defenses by limiting ISG expression, the overall abundance of ISG15 monomer and protein conjugates rises in HCMV-infected cells. However, the molecular signals underlying ISG15 accumulation and whether the ISG15 polypeptide itself influences HCMV infection biology remain unknown. Here, we establish that the ISG15 gene product itself directly regulates HCMV replication and that its accumulation restricts productive virus growth. Although ISG15 monomer and protein conjugate accumulation was induced in cells infected with UV-inactivated HCMV, it was subsequently reduced, but not eliminated, by an immediate-early (IE) or early (E) virus-encoded function(s). Instead, HCMV-induced ISG15 monomer and protein conjugate accumulation was dependent upon the double-stranded DNA (dsDNA) sensor cyclic GMP-AMP synthase (cGAS), the innate immune adaptor STING, and interferon signaling. Significantly, dsDNA itself was sufficient to induce cGAS-, STING-, and interferon signaling-dependent ISG15 monomer and conjugate protein accumulation in uninfected cells. Accumulation of ISGylated proteins in uninfected cells treated with dsDNA was prevented by expressing the HCMV multifunctional IE1 transactivator. This demonstrates that expression of a single host interferon-stimulated gene, ISG15, restricts HCMV replication, and that IE1 is sufficient to blunt ISGylation in response to dsDNA sensing in uninfected cells. Moreover, it establishes that ISGylation modifies the proteomes of virus-infected and uninfected normal cells in response to cell-intrinsic dsDNA sensing dependent upon cGAS-STING.IMPORTANCE By antagonizing type I interferon production and action, many viruses, including human cytomegalovirus (HCMV), evade host defenses. However, levels of the interferon-induced ISG15 protein, which is covalently conjugated to host and viral proteins, increase in HCMV-infected cells. How ISG15 accumulation is regulated and whether the ISG15 polypeptide influences HCMV replication remain unknown. This study establishes that ISG15 itself restricts HCMV replication and that HCMV-induced ISG15 accumulation is triggered by host defenses that detect cytoplasmic double-stranded DNA (dsDNA). Remarkably, dsDNA triggered ISG15 accumulation even in uninfected cells, and this was reduced by HCMV IE1 expression. This shows that ISG15 itself controls the replication of HCMV, which causes life-threatening disease among the immunocompromised and is a significant source of congenital morbidity and mortality among newborns. Moreover, it demonstrates that ISG15 modifies the uninfected cell proteome in response to dsDNA, potentially impacting responses to DNA vaccines, gene therapy, and autoimmune disease pathogenesis.
journal_name
J Viroljournal_title
Journal of virologyauthors
Bianco C,Mohr Idoi
10.1128/JVI.02483-16subject
Has Abstractpub_date
2017-04-13 00:00:00issue
9eissn
0022-538Xissn
1098-5514pii
JVI.02483-16journal_volume
91pub_type
杂志文章abstract::Previous studies using wild-type Encephalomyocarditis virus (EMCV) and Mengo virus, which have long poly(C) tracts (61 to 146 C's) at the 5' nontranslated region of the genome, and variants of these viruses genetically engineered to truncate or substitute the poly(C) tracts have produced conflicting data on the role o...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.77.17.9136-9146.2003
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abstract::Propagation of the flavivirus tick-borne encephalitis virus in BHK-21 cells selected for mutations within the large surface glycoprotein E that increased the net positive charge of the protein. In the course of 16 independent experiments, 12 different protein E mutation patterns were identified. These were located in ...
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pub_type: 杂志文章
doi:10.1128/JVI.75.12.5627-5637.2001
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abstract::Herpes simplex virus 1 (HSV-1) establishes lifelong latent infections in neurons. Reactivation from latency can lead to serious recurrent disease, including stromal keratitis, corneal scarring, blindness, and encephalitis. Although numerous studies link stress to an increase in the incidence of reactivation from laten...
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.73.8.6209-6219.1999
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.78.15.7984-7989.2004
更新日期:2004-08-01 00:00:00
abstract::Growth kinetics in lymphocytic H9 and M8166 cells of two mutants of human immunodeficiency virus type 1 (HIV-1) with deleted gp41 cytoplasmic tails were examined. While the mutant viruses designated CTdel-44 and CTdel-144 were able to grow in M8166 cells, they were unable to grow in H9 cells. Transfection and single-r...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.74.10.4891-4893.2000
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pub_type: 杂志文章
doi:10.1128/JVI.70.6.3753-3762.1996
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.16.2.447-452.1975
更新日期:1975-08-01 00:00:00
abstract::Plasmacytoid dendritic cells (pcDC) and myeloid dendritic cells (myDC) are shown to express CD4 and low levels of CCR5 and CXCR4, but only myDC express DC SIGN, a C-type lectin that binds human immunodeficiency virus but does not mediate virus entry. Both DC types were more susceptible to infection with a macrophage t...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.75.14.6710-6713.2001
更新日期:2001-07-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.15.3.534-539.1975
更新日期:1975-03-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.69.3.1802-1809.1995
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abstract::Herpesvirus saimiri (HVS) is a T-cell-specific transforming and oncogenic virus. A protein encoded by HVS known as Tip-484 (for tyrosine kinase interacting protein from HVS strain 484) is required for this transformation. Tip-484 binds specifically to the nonreceptor protein tyrosine kinase p56lck. By transfecting Tip...
journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.71.1.378-382.1997
更新日期:1997-01-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.12.5875-5881.2002
更新日期:2002-06-01 00:00:00
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journal_title:Journal of virology
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doi:10.1128/JVI.01296-10
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journal_title:Journal of virology
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journal_title:Journal of virology
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doi:10.1128/jvi.77.15.8310-8321.2003
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doi:10.1128/JVI.62.6.1956-1962.1988
更新日期:1988-06-01 00:00:00
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journal_title:Journal of virology
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doi:10.1128/JVI.78.23.13293-13305.2004
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doi:10.1128/JVI.00998-07
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journal_title:Journal of virology
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更新日期:1978-08-01 00:00:00
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journal_title:Journal of virology
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更新日期:2006-01-01 00:00:00
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/jvi.76.3.1475-1487.2002
更新日期:2002-02-01 00:00:00
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更新日期:2000-09-01 00:00:00