The Glycoprotein and Nucleocapsid Protein of Hantaviruses Manipulate Autophagy Flux to Restrain Host Innate Immune Responses

Wang, Kerong; Ma, Heng; Liu, He; Ye, Wei; Li, Zhuo; Cheng, Long; Zhang, Liang; Lei, Yingfeng; Shen, Lixin; Zhang, Fanglin

doi:10.1016/j.celrep.2019.04.061

Cited by 55 publications

(49 citation statements)

References 51 publications

(68 reference statements)

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“…The membranes were incubated with primary antibody against EV71 VP2 (Genetex), followed by incubation with secondary antibody conjugated to an infrared dye (Li-Cor Biosciences, Lincoln, NE, United States). The membranes were visualized using an Odyssey infrared imaging system (Li-Cor Biosciences) as previously described (Wang et al, 2019).…”

Section: Western Blot Analysismentioning

confidence: 99%

Remdesivir (GS-5734) Impedes Enterovirus Replication Through Viral RNA Synthesis Inhibition

Yao

Dong

et al. 2020

Front. Microbiol.

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Human enteroviruses are responsible for diverse diseases, from mild respiratory symptoms to fatal neurological complications. Currently, no registered antivirals have been approved for clinical therapy. Thus, a therapeutic agent for the enterovirus-related disease is urgently needed. Remdesivir (GS-5734) is a novel monophosphoramidate adenosine analog prodrug that exhibits potent antiviral activity against diverse RNA virus families, including positive-sense Coronaviridae and Flaviviridae and negative-sense Filoviridae, Paramyxoviridae, and Pneumoviridae. Currently, remdesivir is under phase 3 clinical development for disease COVID-19 treatment. Here, we found that remdesivir impeded both EV71 viral RNA (vRNA) and complementary (cRNA) synthesis, indicating that EV71 replication is inhibited by the triphosphate (TP) form of remdesivir. Moreover, remdesivir showed potent antiviral activity against diverse enteroviruses. These data extend the remdesivir antiviral activity to enteroviruses and indicate that remdesivir is a promising antiviral treatment for EV71 and other enterovirus infections.

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Section: Western Blot Analysismentioning

confidence: 99%

Remdesivir (GS-5734) Impedes Enterovirus Replication Through Viral RNA Synthesis Inhibition

Yao

Dong

et al. 2020

Front. Microbiol.

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“…SNV, HNTV (Bunyaviridae) Gn Specific colocalization of Gn with LC3-II to selectively degrade the glycoprotein to allow for efficient replication, besides attenuated IFN response, via mitophagy for potential persistence [37,38] (+) RNA viruses DENV, ZIKV (Flaviviridae) NS1, dsRNA…”

Section: Resultsmentioning

confidence: 99%

“…MeV (Paramyxoviridae) C Support viral life cycle by induction of efficient autophagy by recruitment of LC3, Atg5, Atg10 using IRGM and delaying apoptosis to allow for cell-to-cell spread [30,32,33] Maturation: STX17-SNAP29-VAMP8 complex (À) RNA viruses HPIV-3 (Paramyxoviridae) P Phosphoprotein P binds SNAP29 hindering interaction with Stx17 and VAMP8 [26] HNTV (Bunyaviridae) NP Counteracts Gn autophagic degradation by competitive binding to Stx17, thereby preventing autolysosomal fusion during the second wave of autophagy [37] (+) RNA viruses EV-D68, CVB3 (Picornaviridae) IAV proteins found to associate with UVRAG. M2 was found to bind Beclin-1 and thereby prevent autolysosomal fusion and accumulation of autophagosomes [33,44]…”

Section: Resultsmentioning

confidence: 99%

“…Wang et al showed that HTNV Gn interacts with TUFM at mitochondria to dampen type I IFN response through mitophagy and mitochondrial antiviral-signaling protein (MAVS) degradation. More remarkably, at later stages of infection, NP protein prevented Gn autophagic degradation by binding to LC3-II and SNAP29, to disrupt SNAP29-STX17 complex and block SNARE-mediated autophagosome maturation, thereby enhancing viral replication, assembly, and release [37]. HTNV thus induces a first wave of autophagy to escape immune sensing and an incomplete second wave of autophagy, which blocks viral protein degradation.…”

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confidence: 99%

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Escaping the Lion’s Den: redirecting autophagy for unconventional release and spread of viruses

2020

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Autophagy is an evolutionarily conserved process, designed to maintain cellular homeostasis during a range of internal and external stimuli. Conventionally, autophagy is known for coordinated degradation and recycling of intracellular components and removal of cytosolic pathogens. More recently, several lines of evidence have indicated an unconventional, nondegradative role of autophagy for secretion of cargo that lacks a signal peptide. This process referred to as secretory autophagy has also been implicated in the infection cycle of several virus species. This review focuses on the current evidence available on the nondegradative features of autophagy, emphasizing its potential role and unresolved questions in the release and spread of (À) and (+) RNA viruses.

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“…Interestingly, HTNV infection has been shown to induce expression of heat shock protein HSP70 (37), which is a major factor in chaperone-mediated disassembly of SGs (38,39). Also, autophagy is modulated during hantavirus infection, resulting in induction of autophagy at early stages of infection and inhibition of autophagy flux at later stages (40,41). Both these mechanisms could contribute to the observed SG dynamics and to the susceptibility of infected cells to external stress.…”

Section: Discussionmentioning

confidence: 99%

Puumala and Andes Orthohantaviruses Cause Transient Protein Kinase R-Dependent Formation of Stress Granules

Christ

Tynell

Klingström

2020

J Virol

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Virus infection frequently triggers host cell stress signaling resulting in translational arrest; as a consequence, many viruses employ means to modulate the host stress response. Hantaviruses are negative-sense, single-stranded RNA viruses known to inhibit host innate immune responses and apoptosis, but their impact on host cell stress signaling remains largely unknown. In this study, we investigated activation of host cell stress responses during hantavirus infection. We show that hantavirus infection causes transient formation of stress granules (SGs) but does so in only a limited proportion of infected cells. Our data indicate some cell type-specific and hantavirus species-specific variability in SG prevalence and show SG formation to be dependent on the activation of protein kinase R (PKR). Hantavirus infection inhibited PKR-dependent SG formation, which could account for the transient nature and low prevalence of SG formation observed during hantavirus infection. In addition, we report only limited colocalization of hantaviral proteins or RNA with SGs and show evidence indicating hantavirus-mediated inhibition of PKR-like endoplasmic reticulum (ER) kinase (PERK). IMPORTANCE Our work presents the first report on stress granule formation during hantavirus infection. We show that hantavirus infection actively inhibits stress granule formation, thereby escaping the detrimental effects on global translation imposed by host stress signaling. Our results highlight a previously uncharacterized aspect of hantavirus-host interactions with possible implications for how hantaviruses are able to cause persistent infection in natural hosts and for pathogenesis.

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The Glycoprotein and Nucleocapsid Protein of Hantaviruses Manipulate Autophagy Flux to Restrain Host Innate Immune Responses

Cited by 55 publications

References 51 publications

Remdesivir (GS-5734) Impedes Enterovirus Replication Through Viral RNA Synthesis Inhibition

Remdesivir (GS-5734) Impedes Enterovirus Replication Through Viral RNA Synthesis Inhibition

Escaping the Lion’s Den: redirecting autophagy for unconventional release and spread of viruses

Puumala and Andes Orthohantaviruses Cause Transient Protein Kinase R-Dependent Formation of Stress Granules

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