Influenza virus recruits host protein kinase C to control assembly and activity of its replication machinery

Mondal, Arindam; Dawson, Anthony R.; Potts, Gregory K.; Freiberger, Elyse C.; Baker, Steven F.; Moser, Lindsey A.; Bernard, Kristen A.; Coon, Joshua J.; Mehle, Andrew

doi:10.7554/elife.26910

Cited by 60 publications

(68 citation statements)

References 73 publications

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“…Like other viral pathogens, IAV lacks the machinery required for lipid biosynthesis. As it hijacks the host cellular machinery for its replication (17,61), newly assembled IAV acquires its envelope from the host membrane, where sphingolipids are key constituents (62). Previous studies have shown that IAV requires lipid rafts and intact sphingolipid biosynthesis for replication and morphogenesis (62)(63)(64)(65)(66).…”

Section: Discussionmentioning

confidence: 99%

Ceramide Suppresses Influenza A Virus Replication In Vitro

Soudani

Hage‐Sleiman

Karam

et al. 2019

J Virol

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Annual influenza outbreaks are associated with significant morbidity and mortality worldwide despite the availability of seasonal vaccines. Influenza pathogenesis depends on the manipulation of host cell signaling to promote virus replication. Ceramide is a sphingosine-derived lipid that regulates diverse cellular processes. Studies highlighted the differential role of ceramide de novo biosynthesis on the propagation of various viruses. Whether ceramide plays, a role in influenza virus replication is not known. In this study, we assessed the potential interplay between the influenza A (IAV) and ceramide biosynthesis pathways. The accumulation of ceramide in human lung epithelial cells infected with influenza A/H1N1 virus strains was evaluated using thin-layer chromatography and/or confocal microscopy. Virus replication was assessed upon the regulation of the de novo ceramide biosynthesis pathway. A significant increase in ceramide accumulation was observed in cells infected with IAV in a dose-and time-dependent manner. Inoculating the cells with UV-inactivated IAV did not result in ceramide accumulation in the cells, suggesting that the induction of ceramide required an active virus replication. Inhibiting de novo ceramide significantly decreased ceramide accumulation and enhanced virus replication. The addition of exogenous C 6 -ceramide prior to infection mediated an increase in cellular ceramide levels and significantly attenuated IAV replication and reduced viral titers (Ϸ1 log10 PFU/ml unit). Therefore, our data demonstrate that ceramide accumulation through de novo biosynthesis pathway plays a protective and antiviral role against IAV infection. These findings propose new avenues for development of antiviral molecules and strategies. IMPORTANCE Understanding the effect of sphingolipid metabolism on viral pathogenesis provide important insights into the development of therapeutic strategies against microbial infections. In this study, we demonstrate a critical role of ceramide during influenza A virus infection. We demonstrate that ceramide produced through de novo biosynthesis possess an antiviral role. These observations unlock new opportunities for the development of novel antiviral therapies against influenza.

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Section: Discussionmentioning

confidence: 99%

Ceramide Suppresses Influenza A Virus Replication In Vitro

Soudani

Hage‐Sleiman

Karam

et al. 2019

J Virol

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“…Protein interactions were detected by SDS-PAGE and Coomassie staining. Primer extensions were performed using RNA extracted from cells where RNPs were reconstituted without NP using a micro vRNA template (77 nt derived from NP) (Mondal et al, 2017;Turrell et al, 2013).…”

Section: Viruses and Plasmidsmentioning

confidence: 99%

Differential splicing of ANP32A in birds alters its ability to stimulate RNA synthesis by restricted influenza polymerase

Baker

Ledwith

Mehle

2018

Preprint

Self Cite

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Adaptation of viruses to their host can result in specialization and a restricted host range. Species-specific polymorphisms in the influenza virus polymerase restrict its host range during transmission from birds to mammals. ANP32A was recently been identified as a cellular co-factor impacting polymerase adaption and activity. Avian influenza polymerases require ANP32A containing an insertion resulting from an exon duplication uniquely encoded in birds. Here we find that natural splice variants surrounding this exon create avian ANP32A proteins with distinct effects on polymerase activity. We demonstrate species-independent direct interactions between all ANP32A variants and the PB2 polymerase subunit. This interaction is enhanced in the presence of viral genomic RNA. In contrast, only avian ANP32A restored ribonucleoprotein complex assembly for a restricted polymerase by enhancing RNA synthesis. Our data suggest that ANP32A splicing variation amongst birds differentially impacts viral replication, polymerase adaption, and the potential of avian hosts to be reservoirs.

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“…A basic groove separating the head and body domains represents the RNA-binding surface. Phosphorylation and dephosphorylation of NP by cellular kinases and phosphatases affects NP oligomerization and viral replication (Hutchinson et al 2012;Chenavas et al 2013;Mondal et al 2015Mondal et al , 2017Turrell et al 2015). The footprint of NP on vRNA is ∼24 nucleotides (Ortega et al 2000;Hutchinson et al 2012), but it is not known how many nucleotides make direct contact with NP and how the RNA is arranged in vRNPs.…”

Section: Architecture Of Vrnpsmentioning

confidence: 99%

Structure and Function of the Influenza Virus Transcription and Replication Machinery

Fodor

Velthuis

2019

Cold Spring Harb Perspect Med

107

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Transcription and replication of the influenza virus RNA genome is catalyzed by the viral heterotrimeric RNA-dependent RNA polymerase in the context of viral ribonucleoprotein (vRNP) complexes. Atomic resolution structures of the viral RNA synthesis machinery have offered insights into the initiation mechanisms of viral transcription and genome replication, and the interaction of the viral RNA polymerase with host RNA polymerase II, which is required for the initiation of viral transcription. Replication of the viral RNA genome by the viral RNA polymerase depends on host ANP32A, and host-specific sequence differences in ANP32A underlie the poor activity of avian influenza virus polymerases in mammalian cells. A failure to faithfully copy the viral genome segments can lead to the production of aberrant viral RNA products, such as defective interfering (DI) RNAs and mini viral RNAs (mvRNAs). Both aberrant RNA types have been implicated in innate immune responses against influenza virus infection. This review discusses recent insights into the structure-function relationship of the viral RNA polymerase and its role in determining host range and virulence.

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Influenza virus recruits host protein kinase C to control assembly and activity of its replication machinery

Cited by 60 publications

References 73 publications

Ceramide Suppresses Influenza A Virus Replication In Vitro

Ceramide Suppresses Influenza A Virus Replication In Vitro

Differential splicing of ANP32A in birds alters its ability to stimulate RNA synthesis by restricted influenza polymerase

Structure and Function of the Influenza Virus Transcription and Replication Machinery

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