IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses

Lenschow, Deborah J.; Lai, Caroline; Frias-Stäheli, Natalia; Giannakopoulos, Nadia V.; Lutz, Andrew; Wolff, Thorsten; Osiak, Anna; Levine, Beth; Schmidt, Robert E.; García‐Sastre, Adolfo; Leib, David A.; Pekosz, Andrew; Knobeloch, Klaus Peter; Horak, Ivan D.; Virgin, Herbert W.

doi:10.1073/pnas.0607038104

Cited by 483 publications

(453 citation statements)

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“…Interferon-inducible ISG15 has been discovered almost three decades ago [33]. ISG15 is reported important in viral defense and immune response [34,35,36,37,38]. Still, little is known about the molecular mechanisms underlying these functions.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice

et al. 2009

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SummaryGenetic lesions in chromosomal region 3p21.3 marks one of the earliest events in human lung cancer development. It is hypothesized that one or more tumor suppressor genes reside in this region. Identification and characterization of these genes are important for the understanding of lung cancer initiation. UBE1L (UBA7) is a long-suspected 3p21.3 residing tumor suppressor gene. It encodes the key enzyme that activates ISGylation, a novel, ubiquitination-like, post-translational protein modification system that is inducible by interferon. It has been implicated that ISGylation plays a variety of biological roles ranging from viral defense to tumor surveillance. Here we tested the possible function of ISGylation during lung cancer development by using the Ube1l-deficient mice and the K-ras LA2 lung cancer mice. Protein ISGylation levels were largely unchanged during lung cancer progression. Ube1l deficiency neither altered the lung cancer progression nor affected the overall survival of K-ras LA2 lung cancer mice. Our study suggests that Ube1l is not a tumor suppressor gene in K-ras LA2 lung cancer mouse model. However, as described in the discussion, additional studies with other lung cancer mouse models will be necessary to elucidate the potential tumor suppressor function of UBE1L in K-RAS mutation independent human lung cancers.

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Section: Discussionmentioning

confidence: 99%

Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice

et al. 2009

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“…In other systems, the free form of ISG15 has been shown to inhibit the release of Ebola virus-like particles by interfering with the activity of Nedd4 (Malakhova & Zhang, 2008;Okumura et al, 2008). ISGylation is critical to the effect of ISG15 on Sindbis virus, and ISGylation is targeted by the human influenza virus NS1 protein (Yuan & Krug, 2001;Lenschow et al, 2007). As a cytokine, purified ISG15 can activate natural killer and cytotoxic T-cells, stimulate IFN-c production, and induce dendritic cell maturation and neutrophil recruitment (Recht et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…For example, ISG15 can have an antiviral effect on Sindbis virus, influenza virus, HSV, human immunodeficiency virus (HIV) and Ebola virus (Lenschow et al, 2005(Lenschow et al, , 2007Okumura et al, 2006;Zhang et al, 2007), but ISGylation does not contribute to murine susceptibility to lymphocytic choriomeningitis virus and vesicular stomatitis virus , nor to hepatitis B virus replication in ISGylation-deficient mice (Ube1L 2/2 ) (Kim et al, 2008a). Although ISG15 may also promote viral production by acting as a negative regulator of the innate immune response through its conjugation to RIG-I (Kim et al, 2008b), this mechanism is unlikely to contribute to our observed effects, as Huh7.5 cells are deficient in RIG-I (Sumpter et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of ISG15 in IFN-a/b receptor knockout mice protects them from Sindbis virusinduced lethality and decreases Sindbis virus replication in multiple organs (Lenschow et al, 2005). ISG15 2/2 mice are more susceptible to influenza A and B viruses, herpes simplex virus type 1 (HSV-1), Sindbis virus and murine gammaherpesvirus 68 infection; for Sindbis virus, this effect is dependent on ISGylation (Lenschow et al, 2007). Whilst these studies suggest a general role for ISG15 as an antiviral agent, a recent report found that ISG15 can inhibit IFN responses after infection by Newcastle disease virus (Kim et al, 2008a).…”

Section: Introductionmentioning

confidence: 99%

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ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Chen

Sun

Meng

et al. 2009

Journal of General Virology

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Upregulation of interferon (IFN)-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of patients chronically infected with hepatitis C virus (HCV) is associated with subsequent treatment failure (pegylated IFN-a/ribavirin). This study assessed the effect of ISG15 on HCV production in vitro. The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, but ISGylation was inhibited by small interfering RNA directed against the E1 activating enzyme, Ube1L, in Huh7.5 cells. Cells were infected with HCV FL-J6/JFH virus, and HCV RNA and viral titres were determined. Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV were independent of upstream IFN signalling: IFN-a-induced ISG expression was not altered by Ube1L knockdown. Thus, although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent IFN-based treatment failure. INTRODUCTIONHepatitis C virus (HCV) is adept at evading host antiviral mechanisms and is often resistant to the current standard of care -combination treatment with pegylated interferon (IFN)-a and ribavirin (PegIFN/Rib). This regimen eradicates the virus in only 50 % of cases. A number of mechanisms contribute to evasion and treatment resistance, including cleavage of the RIG-I adaptor protein IPS1/ MAVS/Cardif by the HCV NS3/NS4A protease and modulation of the host response by the HCV core protein Loo et al., 2006). However, none of these mechanisms has consistently been demonstrated to play a role in the clinical disease and thus cannot explain the ability of the virus to escape the host response in patients.Response to treatment can be predicted by levels of expression of IFN-stimulated genes (ISGs) in the liver prior to initiation of PegIFN/Rib treatment. Non-responders have increased expression of a number of ISGs (Chen et al., 2005;Feld et al., 2007; Asahina et al., 2008;Asselah et al., 2008;Sarasin-Filipowicz, et al., 2008). Three of these ISGs are components of the ISG15 ubiquitin-like pathway. ISG15 was the first ubiquitin-like protein to be described and, like its homologue ubiquitin, is conjugated to proteins in a tightly regulated process called ISGylation. The ISG15 E1 activating protein, Ube1L, coordinates with the E2 conjugating enzyme (UbcH8) and the E3 ligase (CEB1) to join the C terminus of ISG15 to a wide variety of proteins (Loeb & Haas, 1992). ISG15 can be removed from its target proteins by USP18, an ISG15 protease (Kim et al., 2008b). Thus, ISG15 inhibits virus production for many viruses, but may promote production of some.In this study, we examined the role of ISG15 and ISGylation in HCV production in vitro, using the FL-J6/JFH...

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“…The IFN-inducible 2Ј-5Ј OAS binds dsRNA and synthesizes 2Ј-5Ј-linked oligoadenylates that activate constitutive RNase L to cleave host and viral single-stranded RNA. More recently, antiviral effects have also been attributed to the IFN-␣/␤-inducible proteins Mx, a tryptophan-degrading enzyme (38), adenosine deaminase (34), ISG20 (13, 56), p56 (51, 56), ISG15 (28,29,40), viperin (56), mGBP2 (6), GBP-1 (1), the APOBEC proteins (50), and other, as-yet-undescribed, factors (43,57).In the present study, we provide evidence that a potent PKR-independent translation inhibiting activity is stimulated …”

mentioning

confidence: 99%

Alpha/Beta Interferon Inhibits Cap-Dependent Translation of Viral but Not Cellular mRNA by a PKR-Independent Mechanism

Tesfay

Yin

Gardner

et al. 2008

J Virol

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The alpha/beta interferon (IFN-␣/␤) response is critical for host protection against disseminated replication of many viruses, primarily due to the transcriptional upregulation of genes encoding antiviral proteins. Previously, we determined that infection of mice with Sindbis virus (SB) could be converted from asymptomatic to rapidly fatal by elimination of this response (K. Pathogenesis studies with mice deficient in receptors for alpha/beta interferon (IFN-␣/␤) and IFN-␥ have indicated that IFN-mediated innate responses are vital for the protection of mammals from infections caused by diverse virus types, e.g., lymphocytic choriomeningitis virus (4, 50), Theiler's virus (14), influenza virus (17), measles virus (32), vesicular stomatitis virus (48), and several alphaviruses, including Semliki Forest virus (23, 33), Sindbis virus (SB) (41, 42), and Venezuelan equine encephalitis virus (VEEV) (52). Our results with SB indicate that antiviral activities upregulated by IFN-␣/␤ signaling so severely restrict replication of this apathogenic virus in adult mice that it is virtually undetectable, and disease is completely prevented. However, in the absence of a functional IFN-␣/␤ system, adult mice succumb rapidly to fatal SB disease primarily as a result of systemic infection of macrophages and dendritic cells (DCs) (41). The mechanisms through which the IFN response controls alphavirus replication have not been elucidated (8,43,44). Our results have shown that PKR, but not RNase L, plays an early role in limiting virus replication in DCs; however, IFN-␣/␤ signaling in PKR-deficient animals (PKR Ϫ/Ϫ ) can protect them from fatal SB infection and any manifestations of disease. Furthermore, IFN-mediated protection of DCs or murine embryo fibroblast (MEF) cultures derived from PKR Ϫ/Ϫ mice is as potent as in control cultures (44), and virus replication in these cultures is inhibited very early after infection (43).DThe canonical IFN-␣/␤ signaling pathway involves interaction with the heterodimeric IFN-␣/␤ receptor (IFNAR1 and IFNAR2 subunits), activation of Jak1 and Tyk2 kinases, and phosphorylation and heterodimerization of the STAT1 and STAT2 transcription factors. STAT1/2 heterodimers associate with IRF9, forming the ISGF3 complex which translocates to the nucleus and binds to IFN-stimulated response elements, resulting in transcriptional upregulation of genes, some of which possess antiviral activity. The IFN-␣/␤-upregulated antiviral responses have been thought to primarily involve activation of PKR and 2Ј-5Ј oligoadenylate synthetase (2Ј-5Ј OAS) by double-stranded RNA (dsRNA). PKR-mediated antiviral effects have been attributed to phosphorylation of eukaryotic translation initiation factor 2␣ (eIF2␣) and consequent inhibition of host cell and viral translation initiation. In addition, activated PKR plays a role in apoptosis of infected cells (see, for example, reference 54). The IFN-inducible 2Ј-5Ј OAS binds dsRNA and synthesizes 2Ј-5Ј-linked oligoadenylates that activate constitutive RNase L to cleave host and vi...

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IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses

Cited by 483 publications

References 32 publications

Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice

Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Alpha/Beta Interferon Inhibits Cap-Dependent Translation of Viral but Not Cellular mRNA by a PKR-Independent Mechanism

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