C19orf66 is an interferon-induced inhibitor of HCV replication that restricts formation of the viral replication organelle

Kinast, Volker; Płóciennikowska, Agnieszka; Anggakusuma,; Bracht, Thilo; Todt, Daniel; Brown, Richard J. P.; Boldanova, Tujana; Zhang, Yudi; Brüggemann, Yannick; Friesland, Martina; Engelmann, Michael; Vièyres, Gabrielle; Broering, Ruth; Vondran, Florian W. R.; Heim, Markus H.; Sitek, Barbara; Bartenschlager, Ralf; Pietschmann, Thomas; Steinmann, Eike

doi:10.1016/j.jhep.2020.03.047

Cited by 42 publications

(55 citation statements)

References 26 publications

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“…SHFL was also demonstrated to inhibit both viral and cellular mRNAs -1PRF signals in the context of a dual luciferase reporter construct (54). It is important to note that overall cellular translation and protein expression and ISG expression are unchanged in the presence of SHFL overexpression or knockdown in Huh7.5 cells (166), supporting the notion that SHFL antiviral activity is not due to modulating ISG expression or alteration of global translation (166).…”

Section: Shflmentioning

confidence: 83%

“…In uninfected cells, SHFL resides primarily in the cytoplasm in punctate structures, associating with both stress granule and P body proteins in HEK293 and Huh7.5 cells (165,166), but was also more recently identified as an antiviral effector counteracting replication of RNA viruses (27,28,164,167). For example, SHFL broadly inhibits replication of members of the (+) ssRNA virus family Flaviviridae, including all four DENV serotypes, WNV, ZIKV, and HCV (164)(165)(166)168). SHFL also inhibits the virion production of chikungunya virus and SINV, members of the (+) ssRNA virus family Togaviridae.…”

Section: Shflmentioning

confidence: 99%

“…By doing so, SHFL induces lysosomal-mediated degradation of NS3 in ZIKV-infected cells. SHFL is thought to inhibit HCV replication by interfering with the HCV-induced remodeling of the ER, which generates a membranous web that scaffolds assembly of viral replication complexes (166).…”

Section: Shflmentioning

confidence: 99%

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All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes

Yang

2020

Front. Immunol.

103

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Interferon (IFN) signaling induces the expression of a wide array of genes, collectively referred to as IFN-stimulated genes (ISGs) that generally function to inhibit viral replication. RNA viruses are frequently targeted by ISGs through recognition of viral replicative intermediates and molecular features associated with viral genomes, or the lack of molecular features associated with host mRNAs. The ISGs reviewed here primarily inhibit viral replication in an RNA-centric manner, working to sense, degrade, or repress expression of viral RNA. This review focuses on dissecting how these ISGs exhibit multiple antiviral mechanisms, often through use of varied co-factors, highlighting the complexity of the type I IFN response. Specifically, these ISGs can mediate antiviral effects through viral RNA degradation, viral translation inhibition, or both. While the OAS/RNase L pathway globally degrades RNA and arrests translation, ISG20 and ZAP employ targeted RNA degradation and translation inhibition to block viral replication. Meanwhile, SHFL targets translation by inhibiting -1 ribosomal frameshifting, which is required by many RNA viruses. Finally, a number of E3 ligases inhibit viral transcription, an attractive antiviral target during the lifecycle of negative-sense RNA viruses which must transcribe their genome prior to translation. Through this review, we aim to provide an updated perspective on how these ISGs work together to form a complex network of antiviral arsenals targeting viral RNA processes.

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Section: Shflmentioning

confidence: 83%

Section: Shflmentioning

confidence: 99%

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All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes

Yang

2020

Front. Immunol.

103

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“…It is a 33 kDa protein encoded in an eight-exon gene ( C19orf66 ) located on genomic region 19p13.2. The protein has also been referred to as C19orf66 in studies of its role in restricting Kaposi’s sarcoma-associated herpes virus (KSHV) [ 44 ], hepatitis C virus (HCV) [ 45 ] and Zika virus (ZIKV) [ 46 ]; by virtue of its ability to repress the yield of Dengue virus (DENV), it has also been named RyDEN [ 47 ] and interferon-regulated antiviral gene (IRAV) [ 48 ]. In virus replication and –1 PRF reporter gene assays in cells, SHFL was found to be a broad-spectrum inhibitor of –1 PRF [ 43 ] but did not greatly affect replication of the retrovirus murine leukemia virus (MuLV), suggesting that the protein may not inhibit pseudoknot-dependent RT, a related recoding process employed in the expression of the MuLV Gag-Pol polyprotein [ 49 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Viral Programmed Ribosomal Frameshifting and Stop Codon Readthrough by the Host Restriction Factor Shiftless

Napthine

Hill

Nugent

et al. 2021

Viruses

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The product of the interferon-stimulated gene C19orf66, Shiftless (SHFL), restricts human immunodeficiency virus replication through downregulation of the efficiency of the viral gag/pol frameshifting signal. In this study, we demonstrate that bacterially expressed, purified SHFL can decrease the efficiency of programmed ribosomal frameshifting in vitro at a variety of sites, including the RNA pseudoknot-dependent signals of the coronaviruses IBV, SARS-CoV and SARS-CoV-2, and the protein-dependent stimulators of the cardioviruses EMCV and TMEV. SHFL also reduced the efficiency of stop-codon readthrough at the murine leukemia virus gag/pol signal. Using size-exclusion chromatography, we confirm the binding of the purified protein to mammalian ribosomes in vitro. Finally, through electrophoretic mobility shift assays and mutational analysis, we show that expressed SHFL has strong RNA binding activity that is necessary for full activity in the inhibition of frameshifting, but shows no clear specificity for stimulatory RNA structures.

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“…1 ). 11 Analyzing primary human hepatocytes infected with cell-culture-derived HCV (HCVcc) and liver biopsies from 25 patients with chronic HCV infection, the authors revealed significantly increased mRNA expression levels of C19orf66 , that appeared to be largely independent of viral load, METAVIR score and HCV genotype in patients. Consistently, C19orf66 is induced by IFN therapy in patients with HCV, as revealed by computational analysis of liver transcriptomic data.…”

mentioning

confidence: 99%

Interferon revisited: Peering behind the lines of antiviral defense

Virzì

Suarez

Lupberger

2020

Journal of Hepatology

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C19orf66 is an interferon-induced inhibitor of HCV replication that restricts formation of the viral replication organelle

Cited by 42 publications

References 26 publications

All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes

All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes

Modulation of Viral Programmed Ribosomal Frameshifting and Stop Codon Readthrough by the Host Restriction Factor Shiftless

Interferon revisited: Peering behind the lines of antiviral defense

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