Negative Feedback Regulation of RIG-I-Mediated Antiviral Signaling by Interferon-Induced ISG15 Conjugation

Kim, Minjung; Hwang, Sunyoung; Imaizumi, Tadaatsu; Yoo, Joo‐Yeon

doi:10.1128/jvi.01650-07

Cited by 212 publications

(194 citation statements)

References 43 publications

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“…Many proteins are known to modify the RIG-I pathway and the subsequent cytokine signal transduction (34,51,57,58), but the role of miRNA-mediated regulation is only beginning to emerge. Thus, the level of receptor expression is the first and likely effective point at which miRNAs exert their functions, but few studies have focused on the regulation of RIG-I expression by miRNAs (18).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

Zhu

Nie

et al. 2015

The Journal of Immunology

100

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Japanese encephalitis virus (JEV) can target CNS and cause neuroinflammation that is characterized by profound neuronal damage and concomitant microgliosis/astrogliosis. Although microRNAs (miRNAs) have emerged as a major regulatory network with profound effects on inflammatory response, it is less clear how they regulate JEV-induced inflammation. In this study, we found that miR-15b is involved in modulating the JEV-induced inflammatory response. The data demonstrate that miR-15b is upregulated during JEV infection of glial cells and mouse brains. In vitro overexpression of miR-15b enhances the JEV-induced inflammatory response, whereas inhibition of miR-15b decreases it. Mechanistically, ring finger protein 125 (RNF125), a negative regulator of RIG-I signaling, is identified as a direct target of miR-15b in the context of JEV infection. Furthermore, inhibition of RNF125 by miR-15b results in an elevation in RIG-I levels, which, in turn, leads to a higher production of proinflammatory cytokines and type I IFN. In vivo knockdown of virus-induced miR-15b by antagomir-15b restores the expression of RNF125, reduces the production of inflammatory cytokines, attenuates glial activation and neuronal damage, decreases viral burden in the brain, and improves survival in the mouse model. Taken together, our results indicate that miR-15b modulates the inflammatory response during JEV infection by negative regulation of RNF125 expression. Therefore, miR-15b targeting may constitute an interesting and promising approach to control viral-induced neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

Zhu

Nie

et al. 2015

The Journal of Immunology

100

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“…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). Our data suggest that HCV exploits the ISG15/ISGylation pathway to increase HCV production: overexpression of ISG15, which increases ISGylation in Huh7.5 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…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). ISGylation of the antiviral RIG-I enzyme inhibited IFN signalling in MEF cells (Kim et al, 2008b). Thus, ISG15 inhibits virus production for many viruses, but may promote production of some.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

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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“…), endosome/lysosome-localized molecules (Rab7b, 22,23 CLM-3 24 ), gene transcription coactivators (beta-catenin 25 ), antigen-presenting molecules (MHC I and MHC II 26,27 ), and even HSP70, 28 HSP70L1 29 and NGF. 30 Recently, RIG-I signal pathway regulation was extensively investigated; [31][32][33][34] however, the full anti-inflammatory response mechanisms and the precise finetuning of this process still remain incompletely elucidated.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs in the regulation of TLR and RIG-I pathways

2012

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The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.

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Negative Feedback Regulation of RIG-I-Mediated Antiviral Signaling by Interferon-Induced ISG15 Conjugation

Cited by 212 publications

References 43 publications

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

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

MicroRNAs in the regulation of TLR and RIG-I pathways

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