Virus‐induced autophagic degradation of
            <scp>STAT</scp>
            2 as a mechanism for interferon signaling blockade

Avia, Miguel; Rojas, José M.; Miorin, Lisa; Pascual, Elena; Rijn, P.A. van; Martı́n, Verónica; Garcı́a-Sastre, Adolfo; Sevilla, Noemı́

doi:10.15252/embr.201948766

Cited by 28 publications

(55 citation statements)

References 69 publications

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“…The NS5 protein of HCV interacts with STAT1, interfering with its phosphorylation [ 173 ]. Among the Reoviridae family, the NSP1 protein encoded by rotavirus block the phosphorylation of STAT1 [ 174 ], and the NS3 protein encoded by BTV blocks STAT1 phosphorylation [ 175 , 176 ].…”

Section: Viral Evasion Strategies: Blockade Of Ifn Signalingmentioning

confidence: 99%

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Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

Rojas

Alejo

Martı́n

et al. 2020

Cell. Mol. Life Sci.

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Antiviral responses of interferons (IFNs) are crucial in the host immune response, playing a relevant role in controlling viralw infections. Three types of IFNs, type I (IFN-α, IFN-β), II (IFN-γ) and III (IFN-λ), are classified according to their receptor usage, mode of induction, biological activity and amino acid sequence. Here, we provide a comprehensive review of type I IFN responses and different mechanisms that viruses employ to circumvent this response. In the first part, we will give an overview of the different induction and signaling cascades induced in the cell by IFN-I after virus encounter. Next, highlights of some of the mechanisms used by viruses to counteract the IFN induction will be described. And finally, we will address different mechanism used by viruses to interference with the IFN signaling cascade and the blockade of IFN induced antiviral activities.

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Section: Viral Evasion Strategies: Blockade Of Ifn Signalingmentioning

confidence: 99%

“…The proteasome is not the only catabolic cellular machinery that viruses can highjack to degrade signaling components of the IFN signaling pathway. BTV was recently shown to use ubiquitination of its NS3 protein to drive STAT2 degradation by an autophagy-dependent mechanism [ 175 ].…”

Section: Viral Evasion Strategies: Blockade Of Ifn Signalingmentioning

confidence: 99%

Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

Rojas

Alejo

Martı́n

et al. 2020

Cell. Mol. Life Sci.

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“…Further, prime-boost intramuscular vaccination of sheep with a pentavalent cocktail of DISA vaccines for the “European” serotypes 1, 2, 3, 4, and 8 based on the same DISA platform protects against virulent BTV2 or 8, suggesting that sheep are protected for all five serotypes (van Rijn et al personal communication) (Figure 4). Lack of NS3/NS3a protein likely enhances the interferon mediated immune response, since NS3/NS3a counteracts the innate immune response, and in particular the type I interferon (IFN-α/β) pathway by different mechanisms (162–164).…”

Section: Vaccinesmentioning

confidence: 99%

Prospects of Next-Generation Vaccines for Bluetongue

Rijn

Piet²

2019

Front. Vet. Sci.

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Bluetongue (BT) is a haemorrhagic disease of wild and domestic ruminants with a huge economic worldwide impact on livestock. The disease is caused by BT-virus transmitted by Culicoides biting midges and disease control without vaccination is hardly possible. Vaccination is the most feasible and cost-effective way to minimize economic losses. Marketed BT vaccines are successfully used in different parts of the world. Inactivated BT vaccines are efficacious and safe but relatively expensive, whereas live-attenuated vaccines are efficacious and cheap but are unsafe because of under-attenuation, onward spread, reversion to virulence, and reassortment events. Both manufactured BT vaccines do not enable differentiating infected from vaccinated animals (DIVA) and protection is limited to the respective serotype. The ideal BT vaccine is a licensed, affordable, completely safe DIVA vaccine, that induces quick, lifelong, broad protection in all susceptible ruminant species. Promising vaccine candidates show improvement for one or more of these main vaccine standards. BTV protein vaccines and viral vector vaccines have DIVA potential depending on the selected BTV antigens, but are less effective and likely more costly per protected animal than current vaccines. Several vaccine platforms based on replicating BTV are applied for many serotypes by exchange of serotype dominant outer shell proteins. These platforms based on one BTV backbone result in attenuation or abortive virus replication and prevent disease by and spread of vaccine virus as well as reversion to virulence. These replicating BT vaccines induce humoral and T-cell mediated immune responses to all viral proteins except to one, which could enable DIVA tests. Most of these replicating vaccines can be produced similarly as currently marketed BT vaccines. All replicating vaccine platforms developed by reverse genetics are classified as genetic modified organisms. This implies extensive and expensive safety trails in target ruminant species, and acceptance by the community could be hindered. Nonetheless, several experimental BT vaccines show very promising improvements and could compete with marketed vaccines regarding their vaccine profile, but none of these next generation BT vaccines have been licensed yet.

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“…After a 72-h infection with BTVs at a MOI of 10, the morphologic changes of all the cell lines, including HPTEC, were examined with the help of a microscope. The cells were subsequently collected and prepared for ultramicroscopic analysis by electron microscopy (EM; Hitachi H-600, Japan) as described previously [ 17 ]. The intracellular multiplication of BTVs was also examined to confirm the selective oncolytic effect of BTVs on human renal cancer cells.…”

Section: Methodsmentioning

confidence: 99%

Bluetongue Viruses Act as Novel Oncolytic Viruses to Effectively Inhibit Human Renal Cancer Cell Growth In Vitro and In Vivo

et al. 2021

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Background The bluetongue virus (BTV) is the prototype virus in the genus Orbivirus within the family Reoviridae. Recent studies indicate that BTVs are capable of infecting and selectively lysing human hepatic carcinoma cells (Hep-3B) and prostate carcinoma cells (pc-3). This study was designed to evaluate the oncolytic potential of BTV in experimental models of human renal cancer in vitro and in vivo . Material/Methods Five human renal cancer cell lines, ACHN, CAKI-1, OS-RC-2, 786-O, and A498, were used in this study to analyze BTV replication. These cells were lysed by oncolysis compared to normal control. Xenograft models were used to assess the efficacy and toxicity of BTVs in vivo . Data were analyzed by one-way ANOVA or two-sided unpaired t tests. Results The results showed HPTEC cells to be relatively resistant to cytotoxic effects of BTVs and exhibited normal growth rate even at high dose of BTVs. Nonetheless, the renal cancer cells showed a remarkably higher sensitivity to BTVs. Moreover, the ultramicroscopic subcellular changes were also detected in the renal cells. The viral particles were observed in all the RCC cell lines, but not in HPTEC cells. Intratumoral injections of BTVs significantly decreased the tumor volume as compared to animals that received no virus treatment. Infection with BTVs significantly increased the percentage of apoptotic renal cancer cells but not the HPTEC cells. Moreover, BTV triggered apoptosis in renal cancer cells via a mitochondria-mediated pathway. Conclusions This study for the first time demonstrated the oncolytic potential of BTV in experimental models of human renal cancer. BTV exhibits the potential to inhibit human renal cancer cell growth in vitro and in vivo.

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Virus‐induced autophagic degradation of STAT 2 as a mechanism for interferon signaling blockade

Cited by 28 publications

References 69 publications

Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

Prospects of Next-Generation Vaccines for Bluetongue

Bluetongue Viruses Act as Novel Oncolytic Viruses to Effectively Inhibit Human Renal Cancer Cell Growth In Vitro and In Vivo

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