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The ubiquitin ligase Riplet is essential for RIG-I-dependent innate immune responses to RNA virus infection.
Cell Host Microbe. 2010 Dec 16; 8(6):496-509
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05 Jan 2011
Shizuo Akira
F1000 Immunology
World Premier International Immunology Frontier Research Center, Osaka University,
Osaka, Japan.
F1000 Immunology
World Premier International Immunology Frontier Research Center, Osaka University,
Osaka, Japan.
DOI: 10.3410/f.7269960.7518059
This article is of interest because it revealed that the ubiquitin ligase Riplet is required for in vivo antiviral innate immune responses to certain RNA viruses that are sensed by RIG-I.
The authors previously demonstrated that Riplet targets RIG-I, a sensor for RNA viruses, for lysine 63-linked p leading...Continue reading
The authors previously demonstrated that Riplet targets RIG-I, a sensor for RNA viruses, for lysine 63-linked p leading...Continue reading
This article is of interest because it revealed that the ubiquitin ligase Riplet is required for in vivo antiviral innate immune responses to certain RNA viruses that are sensed by RIG-I.
The authors previously demonstrated that Riplet targets RIG-I, a sensor for RNA viruses, for lysine 63-linked polyubiquitination, leading to activation of RIG-I-dependent signaling pathways. Here, they generated Riplet-deficient mice and found that Riplet-deficient fibroblast cells, macrophages and conventional dendritic cells have defects in production of type I interferon in response to RNA viruses and synthetic RNAs that are recognized by RIG-I, and Riplet-deficient mice are highly susceptible to virus infection. By contrast, Riplet deficiency does not influence cytokine induction following DNA virus infection and various Toll-like receptor agonists stimulation. These findings indicate that Riplet specifically regulates RIG-I-mediated innate immune responses against virus infection in vivo.
The authors previously demonstrated that Riplet targets RIG-I, a sensor for RNA viruses, for lysine 63-linked polyubiquitination, leading to activation of RIG-I-dependent signaling pathways. Here, they generated Riplet-deficient mice and found that Riplet-deficient fibroblast cells, macrophages and conventional dendritic cells have defects in production of type I interferon in response to RNA viruses and synthetic RNAs that are recognized by RIG-I, and Riplet-deficient mice are highly susceptible to virus infection. By contrast, Riplet deficiency does not influence cytokine induction following DNA virus infection and various Toll-like receptor agonists stimulation. These findings indicate that Riplet specifically regulates RIG-I-mediated innate immune responses against virus infection in vivo.
Disclosures
None declared
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Akira S and Kawai T: F1000Prime Recommendation of [Oshiumi H et al., Cell Host Microbe 2010, 8(6):496-509]. In F1000Prime, 05 Jan 2011; DOI: 10.3410/f.7269960.7518059. F1000Prime.com/7269960#eval7518059
07 Jan 2011
DOI: 10.3410/f.7269960.7555055
This paper provides strong genetic evidence that Riplet (also known as RNF135 or REUL) is important for signaling by the RIG-I antiviral pathway. This study also raises the interesting question of why RIG-I activation requires two ubiquitin ligases, TRIM25 and Riplet.
The authors engineered a mouse...Continue reading
The authors engineered a mouse...Continue reading
This paper provides strong genetic evidence that Riplet (also known as RNF135 or REUL) is important for signaling by the RIG-I antiviral pathway. This study also raises the interesting question of why RIG-I activation requires two ubiquitin ligases, TRIM25 and Riplet.
The authors engineered a mouse line lacking Riplet by gene targeting. The homozygous mutant mice developed normally, but MEF cells generated from these mice failed to induce type-I interferons and other cytokines in response to infection with vesicular stomatitis virus (VSV) and 'flu viruses or transfection of RIG-I RNA ligands. The deletion of Riplet did not impair interferon induction by MDA5 or a constitutively active form of RIG-I (N-terminus of RIG-I), nor did it affect interferon induction by cytosolic DNA or LPS. The RIG-I signaling defects in Riplet knockout cells could be rescued by wild type Riplet but not a mutant lacking a RING domain, suggesting that the ubiquitin E3 activity of Riplet is important. The Riplet-deficient mice were compromised in their immune defense against VSV infection in vivo. Together, these results indicate that Riplet is required for RIG-I signaling. Since both TRIM25 and Riplet have been suggested to function as the ubiquitin E3 ligases for K63 polyubiquitination of RIG-I, and deletion of either TRIM25 or Riplet appears to abrogate RIG-I signaling, future studies should elucidate the mechanisms by which TRIM25 and Riplet function together to mediate RIG-I activation.
The authors engineered a mouse line lacking Riplet by gene targeting. The homozygous mutant mice developed normally, but MEF cells generated from these mice failed to induce type-I interferons and other cytokines in response to infection with vesicular stomatitis virus (VSV) and 'flu viruses or transfection of RIG-I RNA ligands. The deletion of Riplet did not impair interferon induction by MDA5 or a constitutively active form of RIG-I (N-terminus of RIG-I), nor did it affect interferon induction by cytosolic DNA or LPS. The RIG-I signaling defects in Riplet knockout cells could be rescued by wild type Riplet but not a mutant lacking a RING domain, suggesting that the ubiquitin E3 activity of Riplet is important. The Riplet-deficient mice were compromised in their immune defense against VSV infection in vivo. Together, these results indicate that Riplet is required for RIG-I signaling. Since both TRIM25 and Riplet have been suggested to function as the ubiquitin E3 ligases for K63 polyubiquitination of RIG-I, and deletion of either TRIM25 or Riplet appears to abrogate RIG-I signaling, future studies should elucidate the mechanisms by which TRIM25 and Riplet function together to mediate RIG-I activation.
Disclosures
None declared
Chen Z: F1000Prime Recommendation of [Oshiumi H et al., Cell Host Microbe 2010, 8(6):496-509]. In F1000Prime, 07 Jan 2011; DOI: 10.3410/f.7269960.7555055. F1000Prime.com/7269960#eval7555055
F1000Prime Recommendations, Dissents and Comments for [Oshiumi H et al., Cell Host Microbe 2010, 8(6):496-509]. In F1000Prime, 19 May 2013; F1000Prime.com/7269960
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RNA virus infection is recognized by the RIG-I-like receptors RIG-I and MDA5, which induce antiviral responses including the production of type I interferons (IFNs) and proinflammatory cytokines. RIG-I is regulated by Lys63-linked polyubiquitination, and three E3 ubiquitin ligases, RNF125, TRIM25, and Riplet, are reported to target RIG-I for ubiquitination. To examine the importance of Riplet in vivo, we generated Riplet-deficient mice. Fibroblasts, macrophages, and conventional dendritic cells from Riplet-deficient animals were defective for the production of IFN and other cytokines in response to infection with several RNA viruses. However, Riplet was dispensable for the production of IFN in response to B-DNA and DNA virus infection. Riplet deficiency abolished RIG-I activation during RNA virus infection, and the mutant mice were more susceptible to vesicular stomatitis virus infection than wild-type mice. These data indicate that Riplet is essential for regulating RIG-I-mediated innate immune response against RNA virus infection in vivo.
Copyright © 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.chom.2010.11.008
PMID: 21147464
