Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125

Arimoto, Kei‐ichiro; Takahashi, Hitoshi; Hishiki, Takayuki; Konishi, Hideyuki; Fujita, Takashi; Shimotohno, Kunitada

doi:10.1073/pnas.0611551104

Cited by 402 publications

(429 citation statements)

References 36 publications

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“…It has been reported that TRIM25 [19] and Riplet/RNF135 [20] act as ubiquitin ligases to activate RIG-I for IFN-b induction in their different sites of RIG-I ubiquitination. Another ubiquitin ligase RNF125 polyubiquitinates RIG-I through Lys48, leading to degradation of RIG-I [21]. The RIG-I level is highly susceptible to not only IFN but also ubiquitination in host cells.…”

Section: Discussionmentioning

confidence: 99%

DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

et al. 2010

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Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR) are members of the DEAD box helicases, and recognize viral RNA in the cytoplasm, leading to IFN-b induction through the adaptor IFN-b promoter stimulator-1 (IPS-1) (also known as Cardif, mitochondrial antiviral signaling protein or virus-induced signaling adaptor). Since uninfected cells usually harbor a trace of RIG-I, other RNA-binding proteins may participate in assembling viral RNA into the IPS-1 pathway during the initial response to infection. We searched for proteins coupling with human IPS-1 by yeast two-hybrid and identified another DEAD (Asp-Glu-AlaAsp) box helicase, DDX3 (DEAD/H BOX 3). DDX3 can bind viral RNA to join it in the IPS-1 complex. Unlike RIG-I, DDX3 was constitutively expressed in cells, and some fraction of DDX3 is colocalized with IPS-1 around mitochondria. The 622-662 a.a DDX3 C-terminal region (DDX3-C) directly bound to the IPS-1 CARD-like domain, and the whole DDX3 protein also associated with RLR. By reporter assay, DDX3 helped IPS-1 up-regulate IFN-b promoter activation and knockdown of DDX3 by siRNA resulted in reduced IFN-b induction. This activity was conserved on the DDX3-C fragment. DDX3 only marginally enhanced IFN-b promoter activation induced by transfected TANK-binding kinase 1 (TBK1) or I-kappa-B kinase-e (IKKe). Forced expression of DDX3 augmented virus-mediated IFN-b induction and host cell protection against virus infection. Hence, DDX3 is an antiviral IPS-1 enhancer. IntroductionRetinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are cytoplasmic RNA helicases [1][2][3], which signal the presence of viral RNA through the adaptor, IFN-b promoter stimulator-1 (IPS-1) (also known as mitochondrial antiviral signaling protein/caspase recruitment domain (CARD) adaptor inducing IFN-b (Cardif)/virus-induced signaling adaptor) to produce . IPS-1 localizes on the outer membrane of the mitochondria via its C-terminus [6]. Its Nterminus consists of a CARD domain, which interacts with the CARD domains of RIG-I and MDA5. Viral RNA resulting from penetration or replication are believed to assemble in the CARDinteracting helicase complex to activate the cytoplasmic IFNinducing pathway. Although non-infected cells usually express minimal amounts of RIG-I/MDA5, the final output of type I IFN is efficiently induced at an early stage of infection to protect host cells from viral spreading.Once IPS-1 is activated, the kinase complex consisting of TANK-homologous proteins and virus-activated kinases induce nuclear translocation of IFN regulatory factor-3 (IRF-3) to activate the IFN promoter [8]. NAK-associated protein 1, TANKbinding kinase 1 (TBK1) and I-kappa-B kinase-e (IKKe) are components of the kinase complex that phosphorylates IRF-3 to induce type I IFN [9,10]. RIG-I recognizes products of various RNA viruses, while MDA5 recognizes products of picornaviruses 940Frontline [1,11]. RIG-I and MDA5 share the helicase domain, which is classified into the DEAD (Asp-Glu-Ala-Asp) box helicase...

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Section: Discussionmentioning

confidence: 99%

DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

et al. 2010

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“…Because miR-15b is overexpressed during JEV infection, and miR-15b functions as a positive regulator of the inflammatory response, we hypothesize that miR-15b represses important suppressors in inflammatory signaling. In this study, we found that miR-15b directly targets RNF125, which was shown to be a negative regulator of RIG-I signaling (34,51). Our data showed that miR-15b markedly inhibits RNF125 expression and promotes the production of inflammatory cytokines by the regulation of RNF125.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…Previous studies showed that RNF125, a ubiquitin ligase, targets RIG-I for proteasomal degradation and, in turn, negatively regulates RIG-I signaling (34,50,51). To study the correlation between RNF125 and RIG-I during JEV infection, the expression patterns of RNF125 and RIG-I were determined.…”

Section: Mir-15b Promotes Rig-i Expression Through Suppression Of Rnf125mentioning

confidence: 99%

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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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“…), 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 regulation of the RIG-I signaling by the ubiquitin ligase RNF125

Cited by 402 publications

References 36 publications

DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

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

MicroRNAs in the regulation of TLR and RIG-I pathways

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