Regulation of flavivirus <scp>RNA</scp> synthesis and capping

Saeedi, Bejan; Geiss, Brian J.

doi:10.1002/wrna.1191

Cited by 34 publications

(31 citation statements)

References 89 publications

(118 reference statements)

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“…A previous study demonstrated that the synthesis of negative-sense RNA primarily depends on NS5 RdRp activity, whereas the synthesis of positive-sense RNA requires multiple additional enzymatic functions from both NS3 (helicase, ATPase, RNA triphosphatase) and NS5 (guanylyltransferase, methyltransferase) (46). Although there is no evidence so far showing that PKA directly phosphorylates NS5, it has been shown that NS5 could indeed be phosphorylated at Thr 449 in the RdRp fingers domain by protein kinase G, leading to the inactivation of its function (55).…”

Section: Discussionmentioning

confidence: 99%

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Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

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The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application.IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV strains tested with minimal cytotoxicity to human endothelial cells and astrocytes, two key cell types for ZIKV infection. Furthermore, we show that PKI inhibits ZIKV negative-sense RNA synthesis and viral protein translation. This study has identified a potent inhibitor of ZIKV infection which could be further explored for future therapeutic application.

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Section: Discussionmentioning

confidence: 99%

“…9C), confirming that PKI mainly affects negative-sense RNA synthesis. Since the negative-sense RNA of flaviviruses often requires NS5 RNA-dependent RNA polymerase (RdRp) activity (46), further investigation can focus on whether and how PKI suppresses the ZIKV NS5 RdRp function.…”

Section: Pki 14-22 Inhibits Zikv Replication By Inhibiting the Pka Pamentioning

confidence: 99%

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Cheng

Silva

Huang

et al. 2018

J Virol

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“…Translation of the long open reading frame produces a large polyprotein that is cleaved by a combination of viral and host proteases to generate three structural proteins and seven nonstructural (NS) proteins (Chambers et al, 1990). The seven NS proteins make up the RNA replication complex that is responsible for generating both the minus- and positive-strands of RNA necessary to carry out the viral life cycle (Saeedi & Geiss, 2013; Westaway et al, 2003). …”

Section: Flavivirus Ns1 Protein: Oligomeric States Drive Functionalitmentioning

confidence: 99%

Oligomeric viral proteins: small in size, large in presence

Jayaraman

Smith

Fernandes

et al. 2016

Critical Reviews in Biochemistry and Molecular Biology

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Viruses are obligate parasites that rely heavily on host cellular processes for replication. The small number of proteins typically encoded by a virus is faced with selection pressures that lead to the evolution of distinctive structural properties, allowing each protein to maintain its function under constraints such as small genome size, high mutation rate, and rapidly changing fitness conditions. One common strategy for this evolution is to utilize small building blocks to generate protein oligomers that assemble in multiple ways, thereby diversifying protein function and regulation. In this review, we discuss specific cases that illustrate how oligomerization is used to generate a single defined functional state, to modulate activity via different oligomeric states, or to generate multiple functional forms via different oligomeric states.

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“…NS5-Pol (74 kDa) is connected via a flexible short linker to the N-terminal methyltransferase (MTase) domain (30 kDa), which contains two MTase activities and possibly a guanylyltransferase activity (GTase), thus incorporating three of the four reactions necessary to form a type-1 RNA cap at the 5’-end of the nascent +RNA strand [4,5]). The NS5-Pol domain alone displays de novo RdRp activity [9,23–26].…”

Section: Regulatory Elements Within the Ns5 Polymerase Domainmentioning

confidence: 99%

Regulation of Flavivirus RNA synthesis and replication

Selisko

Wang

Harris

et al. 2014

Current Opinion in Virology

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RNA synthesis and replication of the members of the Flavivirus genus (including dengue, West Nile and Japanese encephalitis viruses) is regulated by a wide variety of mechanisms and actors. These include the sequestration of the RNA-dependent RNA polymerase (RdRp) for functions other than RNA synthesis, regulatory interactions with other viral and host proteins within the replication complex (RC), and regulatory elements within the RNA genome itself. In this review, we discuss our current knowledge of the multiple levels at which Flavivirus RNA synthesis is controlled. We aim to bring together two active research fields: the structural and functional biology of individual proteins of the RC and the impressive wealth of knowledge acquired regarding the viral genomic RNA.

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Regulation of flavivirus RNA synthesis and capping

Cited by 34 publications

References 89 publications

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22

Oligomeric viral proteins: small in size, large in presence

Regulation of Flavivirus RNA synthesis and replication

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