Identification of Host Kinase Genes Required for Influenza Virus Replication and the Regulatory Role of MicroRNAs

Bakre, Abhijeet; Andersen, Lauren E.; Meliopoulos, Victoria A.; Coleman, Keegan; Yan, Xiuzhen; Brooks, Paula; Crabtree, Jackelyn; Tompkins, S. Mark; Tripp, Ralph A.

doi:10.1371/journal.pone.0066796

Cited by 50 publications

(38 citation statements)

References 113 publications

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“…PANK4 expression is upregulated by glucose in rat muscle and the M2‐type pyruvate kinase is one of its protein partners . PANK4 was identified as a host gene required for influenza virus replication in multiple influenza‐genome screens, and the participation of PANK4 in flu proliferation was validated by siRNA‐mediated knockdown . Knockdown of PANK4 expression restores the plasma membrane localization of a mutant cystic fibrosis transmembrane conductance regulator .…”

Section: Discussionmentioning

confidence: 99%

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

et al. 2019

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Pantothenate kinase generates 4′‐phosphopantothenate in the first and rate‐determining step of coenzyme A (CoA) biosynthesis. The human genome encodes three well‐characterized and nearly identical pantothenate kinases (PANK1‐3) plus a putative bifunctional protein (PANK4) with a predicted amino‐terminal pantothenate kinase domain fused to a carboxy‐terminal phosphatase domain. Structural and phylogenetic analyses show that all active, characterized PANKs contain the key catalytic residues Glu138 and Arg207 (HsPANK3 numbering). However, all amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate kinase activity. Biochemical analysis corroborates bioinformatic predictions—human PANK4 lacks pantothenate kinase activity. Introducing Glu138Val and Arg207Trp substitutions to the human PANK3 and plant PANK4 abolished their robust pantothenate kinase activity. Introducing both catalytic residues back into human PANK4 restored kinase activity, but only to a low level. This result suggests that epistatic changes to the rest of the protein already reduced the kinase activity prior to mutation of the catalytic residues in the course of evolution. The PANK4 from frog, an anamniote living relative encoding the catalytically active residues, had only a low level of kinase activity, supporting the view that HsPANK4 had reduced kinase activity prior to the catalytic residue substitutions in amniotes. Together, our data show that human PANK4 is a pseudo‐pantothenate kinase—a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. The Glu138Val and Arg207Trp substitutions in amniotes (HsPANK3 numbering) completely deactivated the pantothenate kinase activity that had already been reduced by prior epistatic mutations.

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Section: Discussionmentioning

confidence: 99%

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

et al. 2019

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“…HCV infection enhances miR‐130a levels in hepatoma cells, which in turn inhibits IFITM, and therefore aids in HCV replication [Bhanja et al, ]. As for IAV, host miR‐34c enhances IAV replication through upregulating PLK4 kinase expression [Bakre et al, ], and miR‐146 has been shown to be upregulated during IAV infection and affect viral production [Terrier et al, ].…”

Section: Discussionmentioning

confidence: 99%

Modulation of influenza A virus replication by microRNA‐9 through targeting MCPIP1

Dong

Sun

Zhang

et al. 2016

Journal of Medical Virology

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MicroRNAs (miRNAs), a family of small non-coding RNAs controlling translation and transcription of its target genes, play important roles in the regulation of various biological processes, including viral infection. Influenza A viruses (IAV) infection alters expression of cellular miRNAs, which in turn can modify the cellular environment to facilitate efficient virus replication. In this study, we showed that IAV infection significantly induced miR-9 expression in A549 cells, which occurred earlier than drastic expression of viral matrix (M) and nucleoprotein (NP) genes. Overexpression of miR-9 enhanced viral gene expression and production of infectious progeny, while knockdown of miR-9 significantly inhibited IAV replication in A549 cells. Recent studies have revealed antiviral potential of monocyte chemoattractant protein 1-induced protein 1 (MCPIP1), a PIN-like RNase capable of targeting and degrading viral RNA. Subsequently, we comprehensively confirmed that MCPIP1 functionally inhibited viral M and NP genes expression and progeny production, and also was regulated by miR-9 in A549 cells. Furthermore, MCPIP1 overexpression abrogated miR-9-induced IAV replication. Taken together, our findings indicate a new role of miR-9 induction in IAV infection and suggest IAV may hijack cellular miR-9 to benefit the viral life cycle. J. Med. Virol. 89:41-48, 2017. © 2016 Wiley Periodicals, Inc.

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“…Optical density (OD) values were read at a wavelength of 620 nm using a plate spectrophotometer (Tecan Sapphire 2; Männedorf, Switzerland). The ELISA data were normalized by subtracting background intensity values from the raw data points and converted to a Z-score for scoring positive hits as described previously (12). Hits with a Z-score of Ն3.0 were subjected to further validation in HEp-2c and Vero cells.…”

Section: Cells and Virusesmentioning

confidence: 99%

Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game

Sanden

Wang

Dybdahl‐Sissoko

et al. 2016

J Virol

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Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccinepreventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. IMPORTANCEUsing a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus-host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines. This work describes a platform-enabling technology applicable to most vaccine-preventable diseases. Vaccines are important defenses in the fight against infectious disease. Currently, a complex set of factors such as population dynamics and bioproduction costs limit the ability to provide adequate immunization coverage to many economically distressed countries. The current efforts to eradicate poliovirus exemplify these challenges. The oral polio vaccine (OPV), consisting of attenuated Sabin strains, has reduced the total number of poliomyelitis cases by Ͼ99% since the late 1980s. However, live attenuated strains carry the risk of phenotypic reversion to a neurovirulent "vaccine-derived poliovirus" (VDPV) capable of inducing vaccine-associated paralytic poliomyelitis (VAPP) (1, 2). To prevent the emergence and circulation of VDPVs during the polio eradication effort and beyond, OPV must be replaced by the inactivated poliovirus vaccine (IPV) (3). The cost of IPV, which is approximately $3.00 per dose compared to approximately $0.20 for OPV, is a major o...

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Identification of Host Kinase Genes Required for Influenza Virus Replication and the Regulatory Role of MicroRNAs

Cited by 50 publications

References 113 publications

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

Modulation of influenza A virus replication by microRNA‐9 through targeting MCPIP1

Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game

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