Host ANP32A mediates the assembly of the influenza virus replicase

Carrique, L.; Fan, H.; Walker, Alexander P; Keown, J.R.; Sharps, Jane; Staller, Ecco; Barclay, William; Fodor, Ervin; Grimes, Jonathan M.

doi:10.1038/s41586-020-2927-z

Cited by 110 publications

(232 citation statements)

References 62 publications

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“…The RdRp domain uses the priming loop to stabilize the pppApG initiation product [ 30 ]. Recent structural evidence has also revealed that host protein ANP32A must bind to the RNA polymerase residing in the vRNP in order to recruit a newly synthesized RNA polymerase [ 56 ]. This process leads to the formation of a viral RNA polymerase dimer that likely facilitates the transfer of the emerging 5′ terminus of the nascent strand to the new RNA polymerase and the formation of a cRNP [ 11 , 56 , 57 ].…”

Section: The Viral Rna Polymerase and Mechanisms Of Rna Synthesismentioning

confidence: 99%

“…Recent structural evidence has also revealed that host protein ANP32A must bind to the RNA polymerase residing in the vRNP in order to recruit a newly synthesized RNA polymerase [ 56 ]. This process leads to the formation of a viral RNA polymerase dimer that likely facilitates the transfer of the emerging 5′ terminus of the nascent strand to the new RNA polymerase and the formation of a cRNP [ 11 , 56 , 57 ]. No polyadenylation takes place during cRNA synthesis and elongation continues until the vRNA template has been fully copied, which implies that the 5′ end of the vRNA needs to be released from its binding pocket during cRNA sythesis.…”

Section: The Viral Rna Polymerase and Mechanisms Of Rna Synthesismentioning

confidence: 99%

“…Recent studies showed that the priming loop and the binding of a regulatory polymerase, likely the previously identified trans-activating polymerase, play an important role in controlling this realignment event [ 11 , 31 , 60 , 62 ]. Furthermore, a third polymerase must bind near the product exit channel of the resident RNA polymerase in order to form the new vRNP complex, similar to the mechanism observed for cRNP assembly [ 7 , 56 , 57 , 62 ].…”

Section: The Viral Rna Polymerase and Mechanisms Of Rna Synthesismentioning

confidence: 99%

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Influenza Virus RNA Synthesis and the Innate Immune Response

Weis

Velthuis

2021

Viruses

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Infection with influenza A and B viruses results in a mild to severe respiratory tract infection. It is widely accepted that many factors affect the severity of influenza disease, including viral replication, host adaptation, innate immune signalling, pre-existing immunity, and secondary infections. In this review, we will focus on the interplay between influenza virus RNA synthesis and the detection of influenza virus RNA by our innate immune system. Specifically, we will discuss the generation of various RNA species, host pathogen receptors, and host shut-off. In addition, we will also address outstanding questions that currently limit our knowledge of influenza virus replication and host adaption. Understanding the molecular mechanisms underlying these factors is essential for assessing the pandemic potential of future influenza virus outbreaks.

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Section: The Viral Rna Polymerase and Mechanisms Of Rna Synthesismentioning

confidence: 99%

Section: The Viral Rna Polymerase and Mechanisms Of Rna Synthesismentioning

confidence: 99%

Section: The Viral Rna Polymerase and Mechanisms Of Rna Synthesismentioning

confidence: 99%

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Influenza Virus RNA Synthesis and the Innate Immune Response

Weis

Velthuis

2021

Viruses

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“…ANP32 proteins are known to carry out various roles such as chromatin regulation, phosphatase regulation, involvement in apoptosis and intracellular transport [ 318 ]. ANP32A was initially discovered to be a major co-factor of IAV determining species specificity [ 319 ], mediating the assembly of the IAV replicase [ 320 ].…”

Section: Iav Restriction Factorsmentioning

confidence: 99%

Mammalian and Avian Host Cell Influenza A Restriction Factors

McKellar

Rebendenne

Wencker

et al. 2021

Viruses

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The threat of a new influenza pandemic is real. With past pandemics claiming millions of lives, finding new ways to combat this virus is essential. Host cells have developed a multi-modular system to detect incoming pathogens, a phenomenon called sensing. The signaling cascade triggered by sensing subsequently induces protection for themselves and their surrounding neighbors, termed interferon (IFN) response. This response induces the upregulation of hundreds of interferon-stimulated genes (ISGs), including antiviral effectors, establishing an antiviral state. As well as the antiviral proteins induced through the IFN system, cells also possess a so-called intrinsic immunity, constituted of antiviral proteins that are constitutively expressed, creating a first barrier preceding the induction of the interferon system. All these combined antiviral effectors inhibit the virus at various stages of the viral lifecycle, using a wide array of mechanisms. Here, we provide a review of mammalian and avian influenza A restriction factors, detailing their mechanism of action and in vivo relevance, when known. Understanding their mode of action might help pave the way for the development of new influenza treatments, which are absolutely required if we want to be prepared to face a new pandemic.

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“…Interestingly, the interaction between ANP32A and the viral RNA polymerase is significantly strengthened in the presence of viral RNA (26,33), suggesting that ANP32A binds the RNA polymerase in the context of an RNP. Recent cryo-electron microcopy structures of an influenza C virus RNA polymerase dimer revealed that ANP32A formed a bridge between an RNA polymerase bound to RNA and an apo form of the RNA polymerase (7), suggesting that ANP32A mediates the assembly of the viral replicase complex.…”

Section: Introductionmentioning

confidence: 99%

The host factor ANP32A is required for influenza A virus vRNA and cRNA synthesis

Nilsson-Payant

Velthuis

2021

Preprint

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Influenza A viruses are negative-sense RNA viruses that rely on their own viral replication machinery to replicate and transcribe their segmented single-stranded RNA genome. The viral ribonucleoprotein complexes in which viral RNA is replicated consist of a nucleoprotein scaffold around which the RNA genome is bound, and a heterotrimeric RNA-dependent RNA polymerase that catalyzes viral replication. The RNA polymerase copies the viral RNA (vRNA) via a replicative intermediate, called the complementary RNA (cRNA), and subsequently uses this cRNA to make more vRNA copies. To ensure that new cRNA and vRNA molecules are associated with ribonucleoproteins in which they can be amplified, the active RNA polymerase recruits a second polymerase to encapsidate the cRNA or vRNA. Host factor ANP32A has been shown to be essential for viral replication and to facilitate the formation of a dimer between viral RNA polymerases and differences between mammalian and avian ANP32A proteins are sufficient to restrict viral replication. It has been proposed that ANP32A is only required for the synthesis of vRNA molecules from a cRNA, but not vice versa. However, this view does not match recent molecular evidence. Here we use minigenome assays, virus infections, and viral promoter mutations to demonstrate that ANP32A is essential for both vRNA and cRNA synthesis. Moreover, we show that ANP32 is not only needed for the actively replicating polymerase, but also for the polymerase that is encapsidating nascent viral RNA products. Overall, these results provide new insights into influenza A virus replication and host adaptation.IMPORTANCEZoonotic avian influenza A viruses pose a constant threat to global health and they have the potential to cause highly pathogenic pandemic outbreaks. Species variations in host factor ANP32A play a key role in supporting the activity of avian influenza A virus RNA polymerases in mammalian hosts. Here we show that ANP32A acts at two stages in the influenza A virus replication cycle, supporting recent structural experiments and in line with its essential role. Understanding how ANP32A supports viral RNA polymerase activity and how it supports avian polymerase function in mammalian hosts is important for understanding influenza A virus replication and the development of antiviral strategies against influenza A viruses.

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Host ANP32A mediates the assembly of the influenza virus replicase

Cited by 110 publications

References 62 publications

Influenza Virus RNA Synthesis and the Innate Immune Response

Influenza Virus RNA Synthesis and the Innate Immune Response

Mammalian and Avian Host Cell Influenza A Restriction Factors

The host factor ANP32A is required for influenza A virus vRNA and cRNA synthesis

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