Structure and function of the influenza virus replication machinery and PB1‐F2

Mehle, Andrew; McCullers, Jonathan A.

doi:10.1002/9781118636817.ch8

Cited by 6 publications

(5 citation statements)

References 51 publications

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“…Influenza A virus (IAV) is a member of the Orthomyxoviridae family, composed of eight minus-sense single-stranded RNA (ϪssRNA) segments that make up its genome. Each ϪssRNA segment associates with a viral polymerase and oligomeric nucleoproteins (NPs) to form large ribonucleoprotein (RNP) complexes that direct expression of viral genes and replication and packaging of the viral genome (2,3). The ability of the virus to efficiently express its genes and replicate its genome is key to a successful infection as it enables modulation of the host cell environment by the virus to allow subsequent assembly of progeny virions.…”

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confidence: 99%

Ubiquitination Upregulates Influenza Virus Polymerase Function

Kirui

Mondal

Mehle

2016

J Virol

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The influenza A virus polymerase plays an essential role in the virus life cycle, directing synthesis of viral mRNAs and genomes. It is a trimeric complex composed of subunits PA, PB1, and PB2 and associates with viral RNAs and nucleoprotein (NP) to form higher-order ribonucleoprotein (RNP) complexes. The polymerase is regulated temporally over the course of infection to ensure coordinated expression of viral genes as well as replication of the viral genome. Various host factors and processes have been implicated in regulation of the IAV polymerase function, including posttranslational modifications; however, the mechanisms are not fully understood. Here we demonstrate that ubiquitination plays an important role in stimulating polymerase activity. We show that all protein subunits in the RNP are ubiquitinated, but ubiquitination does not significantly alter protein levels. Instead, ubiquitination and an active proteasome enhance polymerase activity. Expression of ubiquitin upregulates polymerase function in a dose-dependent fashion, causing increased accumulation of viral RNA (vRNA), cRNA, and mRNA and enhanced viral gene expression during infection. Ubiquitin expression directly affects polymerase activity independent of nucleoprotein (NP) or ribonucleoprotein (RNP) assembly. Ubiquitination and the ubiquitin-proteasome pathway play key roles during multiple stages of influenza virus infection, and data presented here now demonstrate that these processes modulate viral polymerase activity independent of protein degradation. IMPORTANCEThe cellular ubiquitin-proteasome pathway impacts steps during the entire influenza virus life cycle. Ubiquitination suppresses replication by targeting viral proteins for degradation and stimulating innate antiviral signaling pathways. Ubiquitination also enhances replication by facilitating viral entry and virion disassembly. We identify here an addition proviral role of the ubiquitin-proteasome system, showing that all of the proteins in the viral replication machinery are subject to ubiquitination and this is crucial for optimal viral polymerase activity. Manipulation of the ubiquitin machinery for therapeutic benefit is therefore likely to disrupt the function of multiple viral proteins at stages throughout the course of infection.

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Ubiquitination Upregulates Influenza Virus Polymerase Function

Kirui

Mondal

Mehle

2016

J Virol

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“…The FLUAV RdRP is a key determinant of host tropism and pathogenicity (36,46,61). We therefore tested the replicative capacity of viruses carrying RNP proteins from a primary human and avian FLUAV strains in Tb 1 Lu cells, A/New York/312/2001 (H1N1; NY312) and A/green-winged teal/OH/175/1986 (H2N1; S009), respectively (Fig.…”

Section: Replication Of Human Influenza a Virus In Bat Cellsmentioning

confidence: 99%

“…The FLUAV RdRP, composed of subunits PB1, PB2, and PA, associates with genomic RNA and the viral nucleoprotein (NP) to form ribonucleoprotein (RNP) complexes that mediate transcription and replication (46). Unlike the replication of most other RNA viruses, the replication of FLUAV occurs in the nucleus of the host cell.…”

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Influenza A Virus Polymerase Is a Site for Adaptive Changes during Experimental Evolution in Bat Cells

Poole

Yú²,

Caì³

et al. 2014

J Virol

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The recent identification of highly divergent influenza A viruses in bats revealed a new, geographically dispersed viral reservoir. To investigate the molecular mechanisms of host-restricted viral tropism and the potential for transmission of viruses between humans and bats, we exposed a panel of cell lines from bats of diverse species to a prototypical human-origin influenza A virus. All of the tested bat cell lines were susceptible to influenza A virus infection. Experimental evolution of human and avian-like viruses in bat cells resulted in efficient replication and created highly cytopathic variants. Deep sequencing of adapted human influenza A virus revealed a mutation in the PA polymerase subunit not previously described, M285K. Recombinant virus with the PA M285K mutation completely phenocopied the adapted virus. Adaptation of an avian virus-like virus resulted in the canonical PB2 E627K mutation that is required for efficient replication in other mammals. None of the adaptive mutations occurred in the gene for viral hemagglutinin, a gene that frequently acquires changes to recognize host-specific variations in sialic acid receptors. We showed that human influenza A virus uses canonical sialic acid receptors to infect bat cells, even though bat influenza A viruses do not appear to use these receptors for virus entry. Our results demonstrate that bats are unique hosts that select for both a novel mutation and a well-known adaptive mutation in the viral polymerase to support replication. IMPORTANCE Bats constitute well-known reservoirs for viruses that may be transferred into human populations

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“…The viral RdRP is composed of the subunits PB1, PB2, and PA. The RdRP assembles large complexes with viral RNA and the viral nucleoprotein (NP) to transcribe and replicate the genome [ 25 ]. Species-specific RdRP activity is an impediment to host switching.…”

Section: Zoonotic Potentialmentioning

confidence: 99%

Unusual Influenza A Viruses in Bats

Mehle

2014

Viruses

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Influenza A viruses infect a remarkably diverse number of hosts. Two completely new influenza A virus subtypes were recently discovered in bats, dramatically expanding the host range of the virus. These bat viruses are extremely divergent from all other known strains and likely have unique replication cycles. Phylogenetic analysis indicates long-term, isolated evolution in bats. This is supported by a high seroprevalence in sampled bat populations. As bats represent ~20% of all classified mammals, these findings suggests the presence of a massive cryptic reservoir of poorly characterized influenza A viruses. Here, we review the exciting progress made on understanding these newly discovered viruses, and discuss their zoonotic potential.

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Structure and function of the influenza virus replication machinery and PB1‐F2

Cited by 6 publications

References 51 publications

Ubiquitination Upregulates Influenza Virus Polymerase Function

Ubiquitination Upregulates Influenza Virus Polymerase Function

Influenza A Virus Polymerase Is a Site for Adaptive Changes during Experimental Evolution in Bat Cells

Unusual Influenza A Viruses in Bats

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