DEXH-Box protein DHX30 is required for optimal function of the zinc-finger antiviral protein

Ye, Peiying; Li, Shufeng; Zhu, Young; Chen, Guifang; Gao, Guangxia

doi:10.1007/s13238-010-0117-8

Cited by 45 publications

(39 citation statements)

References 15 publications

(22 reference statements)

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“…Consistent with this, previous studies have shown that exosome components and RNA helicases interact with ZAP to mediate the antiviral response to MLV (22)(23)(24). Therefore, we focused on the localization of exosome component 5 (EXOSC5, also known as RRP46) (27).…”

Section: Zap Recruits the MLV Transcripts And Exosome Components To Rnasupporting

confidence: 65%

“…ZAP reduces the level of MLV transcripts in the cytosol to suppress MLV infection at the posttranscriptional stage, whereas ZAP does not inhibit the early stage of the MLV infection. ZAP recognizes the MLV transcripts via its CCCHtype zinc-finger domains and binds with RNA helicases and the components of the exosome (an RNA degradation system) to induce the degradation of the MLV transcripts (21)(22)(23)(24)(25). However, it is unclear whether endogenous ZAP is involved in the antiviral response to replication-competent MLV in primary cells.…”

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confidence: 99%

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Zinc-finger antiviral protein mediates retinoic acid inducible gene I–like receptor-independent antiviral response to murine leukemia virus

Lee

Komano

Saitoh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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When host cells are infected by an RNA virus, pattern-recognition receptors (PRRs) recognize the viral RNA and induce the antiviral innate immunity. Toll-like receptor 7 (TLR7) detects the genomic RNA of incoming murine leukemia virus (MLV) in endosomes and mediates the antiviral response. However, the RNA-sensing PRR that recognizes the MLV in the cytosol is not fully understood.Here, we definitively demonstrate that zinc-finger antiviral protein (ZAP) acts as a cytosolic RNA sensor, inducing the degradation of the MLV transcripts by the exosome, an RNA degradation system, on RNA granules. Although the retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) RIG-I and melanoma differentiation-associated protein 5 detect various RNA viruses in the cytosol and induce the type I IFN-dependent antiviral response, RLR loss does not alter the replication efficiency of MLV. In sharp contrast, the loss of ZAP greatly enhances the replication efficiency of MLV. ZAP localizes to RNA granules, where the processing-body and stress-granule proteins assemble. ZAP induces the recruitment of the MLV transcripts and exosome components to the RNA granules. The CCCH-type zincfinger domains of ZAP, which are RNA-binding motifs, mediate its localization to RNA granules and MLV transcripts degradation by the exosome. Although ZAP was known as a regulator of RIG-I signaling in a human cell line, ZAP deficiency does not affect the RIG-I-dependent production of type I IFN in mouse cells. Thus, ZAP is a unique member of the cytosolic RNA-sensing PRR family that targets and eliminates intracellular RNA viruses independently of TLR and RLR family members.host defense | retrovirus | ZC3HAV1

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Section: Zap Recruits the MLV Transcripts And Exosome Components To Rnasupporting

confidence: 65%

mentioning

confidence: 99%

Zinc-finger antiviral protein mediates retinoic acid inducible gene I–like receptor-independent antiviral response to murine leukemia virus

Lee

Komano

Saitoh

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Although a possibility that the attenuated antiviral effect by exosome inhibition was due to a ZAP-independent mechanism could not be completely ruled out, the obvious antiviral attenuation by 5-FU under ZAP-S overexpression and IFN-α induction implied that the exosome activity might be required for ZAP-mediated HBV RNA decay. In fact, previous studies demonstrated that other host enzymes are recruited by ZAP to potentiate retroviral RNA degradation, including RNA helicase p72 and DHX30 for restructuring RNA, polyA ribonuclease (PARN) for trimming the polyA tail of mRNA, and cellular decapping complex for initiating the degradation of the target viral mRNA from the 5′ end [42], [46], [78], [79]. Interestingly, HBV ZRE localizes in close proximity to both termini of pgRNA and to the 3′ end of subgenomic RNA, which it may efficiently direct ZAP and its partners to the RNA degradation initiation sites.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hepatitis B Virus Replication by the Host Zinc Finger Antiviral Protein

et al. 2013

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The zinc finger antiviral protein (ZAP) is a mammalian host restriction factor that inhibits the replication of a variety of RNA viruses, including retroviruses, alphaviruses and filoviruses, through interaction with the ZAP-responsive elements (ZRE) in viral RNA, and recruiting the exosome to degrade RNA substrate. Hepatitis B virus (HBV) is a pararetrovirus that replicates its genomic DNA via reverse transcription of a viral pregenomic (pg) RNA precursor. Here, we demonstrate that the two isoforms of human ZAP (hZAP-L and -S) inhibit HBV replication in human hepatocyte-derived cells through posttranscriptional down-regulation of viral pgRNA. Mechanistically, the zinc finger motif-containing N-terminus of hZAP is responsible for the reduction of HBV RNA, and the integrity of the four zinc finger motifs is essential for ZAP to bind to HBV RNA and fulfill its antiviral function. The ZRE sequences conferring the susceptibility of viral RNA to ZAP-mediated RNA decay were mapped to the terminal redundant region (nt 1820–1918) of HBV pgRNA. In agreement with its role as a host restriction factor and as an innate immune mediator for HBV infection, ZAP was upregulated in cultured primary human hepatocytes and hepatocyte-derived cells upon IFN-α treatment or IPS-1 activation, and in the livers of hepatitis B patients during immune active phase. Knock down of ZAP expression increased the level of HBV RNA and partially attenuated the antiviral effect elicited by IPS-1 in cell cultures. In summary, we demonstrated that ZAP is an intrinsic host antiviral factor with activity against HBV through down-regulation of viral RNA, and that ZAP plays a role in the innate control of HBV replication. Our findings thus shed light on virus-host interaction, viral pathogenesis, and antiviral approaches.

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“…DHX30 was also shown to co-immunoprecipitate with a tagged version of the transcription elongation factor TEFM (Minczuk et al, 2011), further suggesting a role in RNA metabolism. Several isoforms of DHX30 have been described, localizing either to mitochondria (Wang and Bogenhagen, 2006) or to the cytoplasm, where DHX30 plays a role in anti-viral responses (Ye et al, 2010;Zhou et al, 2008), another feature reminiscent of GRSF1 (Kash et al, 2002).…”

Section: Characterization Of the Rna Granule Proteomementioning

confidence: 99%

Mitochondrial RNA Granules Are Centers for Posttranscriptional RNA Processing and Ribosome Biogenesis

Antonická¹,

Shoubridge²

2015

Cell Reports

266

282

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Cytoplasmic RNA granules play a central role in mRNA metabolism, but the importance of mitochondrial RNA granules remains relatively unexplored. We characterized their proteome and found that they contain a large toolbox of proteins dedicated to RNA metabolism. Investigation of four uncharacterized putative RNA-binding proteins-two RNA helicases, DHX30 and DDX28, and two proteins of the Fas-activated serine-threonine kinase (FASTKD) family, FASTKD2 and FASTKD5-demonstrated that both helicases and FASTKD2 are required for mitochondrial ribosome biogenesis. RNA-sequencing (RNA-seq) analysis showed that DDX28 and FASTKD2 bound the 16S rRNA. FASTKD5 is required for maturing precursor mRNAs that are not flanked by tRNAs and that therefore cannot be processed by the canonical mRNA maturation pathway. Silencing FASTKD5 rendered mature COX I mRNA almost undetectable, which severely reduced the synthesis of COX I, resulting in a complex IV assembly defect. These data demonstrate that mitochondrial RNA granules are centers for posttranscriptional RNA processing and the biogenesis of mitochondrial ribosomes.

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DEXH-Box protein DHX30 is required for optimal function of the zinc-finger antiviral protein

Cited by 45 publications

References 15 publications

Zinc-finger antiviral protein mediates retinoic acid inducible gene I–like receptor-independent antiviral response to murine leukemia virus

Zinc-finger antiviral protein mediates retinoic acid inducible gene I–like receptor-independent antiviral response to murine leukemia virus

Inhibition of Hepatitis B Virus Replication by the Host Zinc Finger Antiviral Protein

Mitochondrial RNA Granules Are Centers for Posttranscriptional RNA Processing and Ribosome Biogenesis

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