ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Xue, Binbin; Yang, Darong; Wang, Jingjing; Xu, Yan; Wang, Xiaohong; Qin, Yuwen; Tian, Renyun; Chen, Shengwen; Xie, Qinya; Liu, Nianli; Zhu, Haizhen

doi:10.1128/jvi.00352-16

Cited by 50 publications

(52 citation statements)

References 45 publications

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“…2C to E). Importantly, ISG12a and ISG56 exhibit anti-HCV activity, as reported in our and other previous studies (35)(36)(37). The enhanced expression of ISG12a and ISG56 in NLRX1-silenced cells was consistent with reduced infection by HCV during NLRX1 depletion (Fig.…”

Section: Resultssupporting

confidence: 73%

NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2

Qin

Xue

Liu

et al. 2017

J Virol

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Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. However, attenuation or termination of signaling is also necessary for preventing immune-mediated tissue damage and spontaneous autoimmunity. Here, we identify NLRX1 as a negative regulator for MAVS-mediated signaling pathway during HCV infection. Depletion of NLRX1 enhances HCV-triggered activation of IFN signaling and causes the suppression of HCV propagation in hepatocytes. NLRX1, a HCV-inducible protein, interacts with MAVS and mediates the K48-linked polyubiquitination and the subsequent degradation of MAVS via proteasomal pathway. Moreover, PCBP2 interacts with NLRX1 to participate in NLRX1-induced degradation of MAVS and inhibition of antiviral responses during HCV infection. Mutagenic analyses further revealed that the NOD domain of NLRX1 is essential for NLRX1 to interact with PCBP2 and subsequently induce MAVS degradation. Our study unlocks a key mechanism of fine tuning of innate immunity by which NLRX1 restrains RLRs-MAVS signaling cascade by recruiting PCBP2 to MAVS for inducing MAVS degradation through the proteasomal pathway. NLRX1, a negative regulator of innate immunity, is a pivotal host factor for HCV to establish persistent infection. Innate immunity needs to be tightly regulated to maximize antiviral response and minimize immune-mediated pathology. Whereas, the underlying mechanisms are poorly understood. In this study, we report that NLRX1 is a proviral host factor for HCV infection and functions as a negative regulator in HCV-triggered innate immune response. NLRX1 recruits PCBP2 to MAVS and induces the K48-linked polyubiquitination and degradation of MAVS, leading to the negative regulation of IFN signaling pathway and promoting HCV infection. Overall, this study provides intriguing insights into how innate immunity is regulated during viral infection.

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Section: Resultssupporting

confidence: 73%

NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2

Qin

Xue

Liu

et al. 2017

J Virol

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“…In addition, the possible interaction between IFI6 and several viral replicase proteins that was tested using immunoprecipitation and did not yield any significant results. ISG12a, an IFI6-related protein, inhibits hepatitis C virus by degrading nonstructural protein NS5A (36). IFI6 activation, however, did not seem to affect the stability of several tested ZIKV proteins.…”

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confidence: 90%

A CRISPR Activation Screen Identifies Genes That Protect against Zika Virus Infection

Dukhovny

Lamkiewicz

Qian

et al. 2019

J Virol

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Zika virus (ZIKV) is an arthropod-borne emerging pathogen causing febrile illness. ZIKV is associated Guillain-Barré syndrome and other neurological complications. Infection during pregnancy is associated with pregnancy complications and developmental and neurological abnormalities collectively defined as congenital Zika syndrome. There is still no vaccine or specific treatment for ZIKV infection. To identify host factors that can rescue cells from ZIKV infection, we used a genomescale CRISPR activation screen. Our highly ranking hits included a short list of interferon-stimulated genes (ISGs) previously reported to have antiviral activity. Validation of the screen results highlighted interferon lambda 2 (IFN-2) and interferon alpha-inducible protein 6 (IFI6) as genes providing high levels of protection from ZIKV. Activation of these genes had an effect on an early stage in viral infection. In addition, infected cells expressing single guide RNAs (sgRNAs) for both of these genes displayed lower levels of cell death than did the controls. Furthermore, the identified genes were significantly induced in ZIKV-infected placenta explants. Thus, these results highlight a set of ISGs directly relevant for rescuing cells from ZIKV infection or its associated cell death and substantiate CRISPR activation screens as a tool to identify host factors impeding pathogen infection. IMPORTANCE Zika virus (ZIKV) is an emerging vector-borne pathogen causing a febrile disease. ZIKV infection might also trigger Guillain-Barré syndrome, neuropathy, and myelitis. Vertical transmission of ZIKV can cause fetus demise, stillbirth, or severe congenital abnormalities and neurological complications. There is no vaccine or specific antiviral treatment against ZIKV. We used a genome-wide CRISPR activation screen, where genes are activated from their native promoters to identify host cell factors that protect cells from ZIKV infection or associated cell death. The results provide a better understanding of key host factors that protect cells from ZIKV infection and might assist in identifying novel antiviral targets.

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“…Their human ISG orthologues IFI6 and IFI27 (aka ISG12A) are internal membrane proteins stabilizing ER membrane and preventing the formation of flavivirus-induced ER membrane invaginations (74) or destabilize mitochondrial membrane and promote apoptosis (75). In fact, IFI27 can also recruit a E3 ubiquitin ligase and targets HCV NS5 protein to degradation (76), illustrating the potential diversity of antiviral mechanisms mediated by members of this family.…”

Section: Discussionmentioning

confidence: 99%

Interferon-stimulated genes in zebrafish and human define an ancient arsenal of antiviral immunity

Levraud

Jouneau

Briolat

et al. 2019

Preprint

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The evolution of the interferon (IFN) system, the major innate antiviral mechanism of vertebrates, remains poorly understood. According to the detection of type I IFN genes in cartilaginous fish genomes, the system appeared 500My ago. However, the IFN system integrates many other components, most of which are encoded by IFN-stimulated genes (ISGs). To shed light on its evolution, we have used deep RNA sequencing to generate a comprehensive list of ISGs of zebrafish, taking advantage of the high quality genome annotation in this species. We analyzed larvae after inoculation of recombinant zebrafish type I IFN, or infection with chikungunya virus, a potent IFN inducer. We identified more than 400 zebrafish ISGs, defined as being either directly induced by IFN or induced by the virus in an IFN receptor-dependent manner. Their human orthologues were highly enriched in ISGs, particularly for highly-inducible genes. We identified 72 orthology groups containing ISGs in both zebrafish and human, revealing a core ancestral ISG repertoire, which includes most of the known signaling components of the IFN system. Many downstream effectors were also already present 450 My ago in the common ancestor of tetrapods and bony fish, and diversified as multi-gene families independently in the two lineages. A large proportion of the ISG repertoire is lineage-specific; around 40% of protein-coding zebrafish ISGs had no human orthologue. We identified 14 fish-specific gene families containing multiple ISGs, including finTRIMs. This work illuminates the evolution of the IFN system and provides a rich resource to explore new antiviral mechanisms.Key pointsWe established an exhaustive list of larval zebrafish ISGs.Orthologous ISGs in fish and human identify a large ancestral ISG repertoire.

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ISG12a Restricts Hepatitis C Virus Infection through the Ubiquitination-Dependent Degradation Pathway

Cited by 50 publications

References 45 publications

NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2

NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2

A CRISPR Activation Screen Identifies Genes That Protect against Zika Virus Infection

Interferon-stimulated genes in zebrafish and human define an ancient arsenal of antiviral immunity

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