A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection
Abstract
ABSTRACT Rift Valley fever virus (RVFV) is an arbovirus within theBunyaviridaefamily capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCERVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments ormore »
- Authors:
-
- Sandia National Lab. (SNL-CA), Livermore, CA (United States)
- Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
- Publication Date:
- Research Org.:
- Sandia National Lab. (SNL-CA), Livermore, CA (United States); Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA)
- OSTI Identifier:
- 1326652
- Alternate Identifier(s):
- OSTI ID: 1474355
- Report Number(s):
- SAND-2016-6020J; LLNL-JRNL-738409
Journal ID: ISSN 0022-538X; 642583
- Grant/Contract Number:
- AC04-94AL85000; AC52-07NA27344
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Virology
- Additional Journal Information:
- Journal Volume: 90; Journal Issue: 16; Journal ID: ISSN 0022-538X
- Publisher:
- American Society for Microbiology
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Biological and medical sciences
Citation Formats
Harmon, Brooke, Bird, Sara W., Schudel, Benjamin R., Hatch, Anson V., Rasley, Amy, and Negrete, Oscar A. A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection. United States: N. p., 2016.
Web. doi:10.1128/JVI.00543-16.
Harmon, Brooke, Bird, Sara W., Schudel, Benjamin R., Hatch, Anson V., Rasley, Amy, & Negrete, Oscar A. A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection. United States. https://doi.org/10.1128/JVI.00543-16
Harmon, Brooke, Bird, Sara W., Schudel, Benjamin R., Hatch, Anson V., Rasley, Amy, and Negrete, Oscar A. Wed .
"A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection". United States. https://doi.org/10.1128/JVI.00543-16. https://www.osti.gov/servlets/purl/1326652.
@article{osti_1326652,
title = {A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection},
author = {Harmon, Brooke and Bird, Sara W. and Schudel, Benjamin R. and Hatch, Anson V. and Rasley, Amy and Negrete, Oscar A.},
abstractNote = {ABSTRACT Rift Valley fever virus (RVFV) is an arbovirus within theBunyaviridaefamily capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCERVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. These studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.},
doi = {10.1128/JVI.00543-16},
journal = {Journal of Virology},
number = 16,
volume = 90,
place = {United States},
year = {Wed Jul 27 00:00:00 EDT 2016},
month = {Wed Jul 27 00:00:00 EDT 2016}
}
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Works referenced in this record:
The risk of Rift Valley fever virus introduction and establishment in the United States and European Union
journal, January 2013
- Rolin, Alicia I.; Berrang-Ford, Lea; Kulkarni, Manisha A.
- Emerging Microbes & Infections, Vol. 2, Issue 1
RNA interference screen for human genes associated with West Nile virus infection
journal, August 2008
- Krishnan, Manoj N.; Ng, Aylwin; Sukumaran, Bindu
- Nature, Vol. 455, Issue 7210
Host Cell Factors in HIV Replication: Meta-Analysis of Genome-Wide Studies
journal, May 2009
- Bushman, Frederic D.; Malani, Nirav; Fernandes, Jason
- PLoS Pathogens, Vol. 5, Issue 5
Development and Use of a Vaccinia Virus Neutralization Assay Based on Flow Cytometric Detection of Green Fluorescent Protein
journal, September 2003
- Earl, P. L.; Americo, J. L.; Moss, B.
- Journal of Virology, Vol. 77, Issue 19
RNAi Screening Reveals Proteasome- and Cullin3-Dependent Stages in Vaccinia Virus Infection
text, January 2012
- Mercer, Jason; Snijder, Berend; Sacher, Raphael
- Cell Press (Elsevier)
Dual Functions of Rift Valley Fever Virus NSs Protein: Inhibition of Host mRNA Transcription and Post-transcriptional Downregulation of Protein Kinase PKR
journal, September 2009
- Ikegami, Tetsuro; Narayanan, Krishna; Won, Sungyong
- Annals of the New York Academy of Sciences, Vol. 1171
Animal models of Rift Valley fever virus infection
journal, February 2012
- Ross, Ted M.; Bhardwaj, Nitin; Bissel, Stephanie J.
- Virus Research, Vol. 163, Issue 2
Rift Valley Fever Virus Infection of Human Cells and Insect Hosts Is Promoted by Protein Kinase C Epsilon
journal, November 2010
- Filone, Claire Marie; Hanna, Sheri L.; Caino, M. Cecilia
- PLoS ONE, Vol. 5, Issue 11
A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice
journal, March 2012
- Waaler, J.; Machon, O.; Tumova, L.
- Cancer Research, Vol. 72, Issue 11
High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection
journal, April 2016
- Islam, Md. Koushikul; Baudin, Maria; Eriksson, Jonas
- Journal of Biomolecular Screening, Vol. 21, Issue 4
Development and characterization of a Rift Valley fever virus cell–cell fusion assay using alphavirus replicon vectors
journal, December 2006
- Filone, Claire Marie; Heise, Mark; Doms, Robert W.
- Virology, Vol. 356, Issue 1-2
Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases
journal, July 2009
- MacDonald, Bryan T.; Tamai, Keiko; He, Xi
- Developmental Cell, Vol. 17, Issue 1
Can we safely target the WNT pathway?
journal, July 2014
- Kahn, Michael
- Nature Reviews Drug Discovery, Vol. 13, Issue 7
Safely targeting cancer stem cells via selective catenin coactivator antagonism
journal, September 2014
- Lenz, Heinz-Josef; Kahn, Michael
- Cancer Science, Vol. 105, Issue 9
Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex
journal, June 2012
- Li, Vivian S. W.; Ng, Ser Sue; Boersema, Paul J.
- Cell, Vol. 149, Issue 6
Wnt/beta-Catenin Signaling and Small Molecule Inhibitors
journal, December 2012
- Voronkov, Andrey; Krauss, Stefan
- Current Pharmaceutical Design, Vol. 19, Issue 4, p. 634-664
The Pathogenesis of Rift Valley Fever
journal, May 2011
- Ikegami, Tetsuro; Makino, Shinji
- Viruses, Vol. 3, Issue 5
Targeting the Wnt pathway in human cancers: Therapeutic targeting with a focus on OMP-54F28
journal, February 2015
- Le, Phuong N.; McDermott, Jessica D.; Jimeno, Antonio
- Pharmacology & Therapeutics, Vol. 146
Hepatitis C virus core protein activates Wnt/β-catenin signaling through multiple regulation of upstream molecules in the SMMC-7721 cell line
journal, February 2011
- Liu, Jiao; Wang, Zengchan; Tang, Jia
- Archives of Virology, Vol. 156, Issue 6
Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled
journal, April 2009
- Grandy, David; Shan, Jufang; Zhang, Xinxin
- Journal of Biological Chemistry, Vol. 284, Issue 24
Rift Valley Fever Virus NSs mRNA Is Transcribed from an Incoming Anti-Viral-Sense S RNA Segment
journal, August 2005
- Ikegami, T.; Won, S.; Peters, C. J.
- Journal of Virology, Vol. 79, Issue 18
Emerging links between CDK cell cycle regulators and Wnt signaling
journal, August 2010
- Davidson, Gary; Niehrs, Christof
- Trends in Cell Biology, Vol. 20, Issue 8
Wnt/β-Catenin Signaling and Disease
journal, June 2012
- Clevers, Hans; Nusse, Roel
- Cell, Vol. 149, Issue 6
Hepatitis B virus X protein is essential for the activation of Wnt/?-catenin signaling in hepatoma cells
journal, January 2004
- Cha, Man-Young; Kim, Chang-Myeong; Park, Young-Min
- Hepatology, Vol. 39, Issue 6
Genome-Wide Small Interfering RNA Screens Reveal VAMP3 as a Novel Host Factor Required for Uukuniemi Virus Late Penetration
journal, May 2014
- Meier, R.; Franceschini, A.; Horvath, P.
- Journal of Virology, Vol. 88, Issue 15
Enhancement of Canonical Wnt/β-Catenin Signaling Activity by HCV Core Protein Promotes Cell Growth of Hepatocellular Carcinoma Cells
journal, November 2011
- Liu, Jiao; Ding, Xiong; Tang, Jia
- PLoS ONE, Vol. 6, Issue 11
A Whole-Genome RNA Interference Screen for Human Cell Factors Affecting Myxoma Virus Replication
journal, February 2013
- Teferi, W. M.; Dodd, K.; Maranchuk, R.
- Journal of Virology, Vol. 87, Issue 8
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
journal, December 2008
- Huang, Da Wei; Sherman, Brad T.; Lempicki, Richard A.
- Nature Protocols, Vol. 4, Issue 1
Rift Valley Fever Virus Strain MP-12 Enters Mammalian Host Cells via Caveola-Mediated Endocytosis
journal, September 2012
- Harmon, B.; Schudel, B. R.; Maar, D.
- Journal of Virology, Vol. 86, Issue 23
Host Cell Factors in HIV Replication: Meta-Analysis of Genome-Wide Studies
text, January 2009
- Bushman, Frederic D.; Fernandes, Jason; D'Orso, Ivan
- Columbia University
Human Cytomegalovirus Infection Dysregulates the Canonical Wnt/β-catenin Signaling Pathway
journal, October 2012
- Angelova, Magdalena; Zwezdaryk, Kevin; Ferris, MaryBeth
- PLoS Pathogens, Vol. 8, Issue 10
Development and Use of a Vaccinia Virus Neutralization Assay Based on Flow Cytometric Detection of Green Fluorescent Protein
journal, December 2003
- Earl, Patricia L.; Americo, Jeffrey L.; Moss, Bernard
- Journal of Virology, Vol. 77, Issue 23
Illustration of SSMD, z Score, SSMD*, z* Score, and t Statistic for Hit Selection in RNAi High-Throughput Screens
journal, April 2011
- Zhang, X. D.
- Journal of Biomolecular Screening, Vol. 16, Issue 7
Wnt Modulating Agents Inhibit Human Cytomegalovirus Replication
journal, April 2013
- Kapoor, Arun; He, Ran; Venkatadri, Rajkumar
- Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 6
Microfluidic platforms for RNA interference screening of virus–host interactions
journal, January 2013
- Schudel, Benjamin R.; Harmon, Brooke; Abhyankar, Vinay V.
- Lab on a Chip, Vol. 13, Issue 5
A genome-wide RNAi screen reveals that mRNA decapping restricts bunyaviral replication by limiting the pools of Dcp2-accessible targets for cap-snatching
journal, July 2013
- Hopkins, K. C.; McLane, L. M.; Maqbool, T.
- Genes & Development, Vol. 27, Issue 13
Wnt signalling and its impact on development and cancer
journal, May 2008
- Klaus, Alexandra; Birchmeier, Walter
- Nature Reviews Cancer, Vol. 8, Issue 5
Signatures of Host mRNA 5′ Terminus for Efficient Hantavirus Cap Snatching
journal, July 2012
- Cheng, Erdong; Mir, Mohammad A.
- Journal of Virology, Vol. 86, Issue 18
Bunyavirus: Structure and Replication
book, January 2011
- Guu, Tom S. Y.; Zheng, Wenjie; Tao, Yizhi J.
- Viral Molecular Machines
Regulation of the Interaction between Glycogen Synthase Kinase 3 and the Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen
journal, July 2005
- Fujimuro, M.; Liu, J.; Zhu, J.
- Journal of Virology, Vol. 79, Issue 16
RNAi screening reveals proteasome- and Cullin3-dependent stages in vaccinia virus infection.
text, January 2012
- Bleck, Christopher Karl Ernst; Burkard, Christine; Snijder, Berend
- Elsevier
Wnt/beta-Catenin Signaling and Small Molecule Inhibitors
journal, February 2013
- Voronkov, Andrey; Krauss, Stefan
- Current Pharmaceutical Design, Vol. 19, Issue 4
What have RNAi screens taught us about viral–host interactions?
journal, August 2009
- Cherry, Sara
- Current Opinion in Microbiology, Vol. 12, Issue 4
The N Terminus of Rift Valley Fever Virus Nucleoprotein Is Essential for Dimerization
journal, August 2005
- Le May, N.; Gauliard, N.; Billecocq, A.
- Journal of Virology, Vol. 79, Issue 18
RNAi Screening Reveals Proteasome- and Cullin3-Dependent Stages in Vaccinia Virus Infection
journal, October 2012
- Mercer, Jason; Snijder, Berend; Sacher, Raphael
- Cell Reports, Vol. 2, Issue 4
Beta-catenin up-regulates the constitutive and virus-induced transcriptional capacity of the interferon-β promoter through T-cell factor binding sites
journal, October 2015
- Marcato, Vasco; Luron, Lionel; Laqueuvre, Lucie M.
- Molecular and Cellular Biology
STRING v9.1: protein-protein interaction networks, with increased coverage and integration
journal, November 2012
- Franceschini, Andrea; Szklarczyk, Damian; Frankild, Sune
- Nucleic Acids Research, Vol. 41, Issue D1
Hepatitis B viral X protein interacts with tumor suppressor adenomatous polyposis coli to activate Wnt/β-catenin signaling
journal, January 2011
- Hsieh, Antony; Kim, Hyeon-Seop; Lim, Seung-Oe
- Cancer Letters, Vol. 300, Issue 2
Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication
journal, January 2010
- Karlas, Alexander; Machuy, Nikolaus; Shin, Yujin
- Nature, Vol. 463, Issue 7282
Identification of Critical Amino Acids within the Nucleoprotein of Tacaribe Virus Important for Anti-interferon Activity
journal, February 2013
- Harmon, Brooke; Kozina, Carol; Maar, Dianna
- Journal of Biological Chemistry, Vol. 288, Issue 12
Conductin/axin2 and Wnt signalling regulates centrosome cohesion
journal, March 2010
- Hadjihannas, Michel V.; Brückner, Martina; Behrens, Jürgen
- EMBO reports, Vol. 11, Issue 4
Nonstructural NSs Protein of Rift Valley Fever Virus Interacts with Pericentromeric DNA Sequences of the Host Cell, Inducing Chromosome Cohesion and Segregation Defects
journal, November 2009
- Mansuroglu, Z.; Josse, T.; Gilleron, J.
- Journal of Virology, Vol. 84, Issue 2
Rift Valley Fever Virus NSs Protein Promotes Post-Transcriptional Downregulation of Protein Kinase PKR and Inhibits eIF2α Phosphorylation
journal, February 2009
- Ikegami, Tetsuro; Narayanan, Krishna; Won, Sungyong
- PLoS Pathogens, Vol. 5, Issue 2
High frequency of SEN virus infection in thalassemic patients and healthy blood donors in Iran
journal, January 2010
- Karimi-Rastehkenari, Abbas; Bouzari, Majid
- Virology Journal, Vol. 7, Issue 1
Interplay Between Wnt/β-Catenin Signaling and HIV: Virologic and Biologic Consequences in the CNS
journal, October 2012
- Al-Harthi, Lena
- Journal of Neuroimmune Pharmacology, Vol. 7, Issue 4
STRING v9.1: protein-protein interaction networks, with increased coverage and integration
text, January 2013
- Franceschini, Andrea; Szklarczyk, Damian; Frankild, Sune
- Oxford University Press
Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen
journal, January 2008
- Brass, Abraham L.; Dykxhoorn, Derek M.; Benita, Yair
- Science, Vol. 319, Issue 5865
Bunyaviral cap-snatching vs. decapping: Recycling cell cycle mRNAs
journal, December 2013
- Hopkins, Kaycie; Cherry, Sara
- Cell Cycle, Vol. 12, Issue 24
Rift Valley fever virus ( Bunyaviridae: Phlebovirus ): an update on pathogenesis, molecular epidemiology, vectors, diagnostics and prevention
journal, May 2010
- Pepin, Michel; Bouloy, Michèle; Bird, Brian H.
- Veterinary Research, Vol. 41, Issue 6
Notch and Wnt Signaling: Mimicry and Manipulation by Gamma Herpesviruses
journal, May 2006
- Hayward, S. Diane; Liu, Jianyong; Fujimuro, Masahiro
- Science's STKE, Vol. 2006, Issue 335
Works referencing / citing this record:
Recent advances in the development of antiviral therapeutics for Rift Valley fever virus infection
journal, November 2017
- Atkins, Colm; Freiberg, Alexander N.
- Future Virology, Vol. 12, Issue 11
HSV-1 single-cell analysis reveals the activation of anti-viral and developmental programs in distinct sub-populations
journal, May 2019
- Drayman, Nir; Patel, Parthiv; Vistain, Luke
- eLife, Vol. 8
Vaccinia virus protein A49 activates Wnt signalling by targetting the E3 ligase β-TrCP.
text, January 2017
- Maluquer De Motes, Carlos; Smith, Geoffrey
- Apollo - University of Cambridge Repository
HSV-1 single cell analysis reveals anti-viral and developmental programs activation in distinct sub-populations
posted_content, March 2019
- Drayman, Nir; Patel, Parthiv; Vistain, Luke
A MicroRNA Screen Identifies the Wnt Signaling Pathway as a Regulator of the Interferon Response during Flavivirus Infection
journal, April 2017
- Smith, Jessica L.; Jeng, Sophia; McWeeney, Shannon K.
- Journal of Virology, Vol. 91, Issue 8
Functions of the WNT Signaling Network in Shaping Host Responses to Infection
journal, November 2019
- Ljungberg, Johanna K.; Kling, Jessica C.; Tran, Thao Thanh
- Frontiers in Immunology, Vol. 10
miR‐193b represses influenza A virus infection by inhibiting Wnt/β‐catenin signalling
journal, January 2019
- Yang, Xiaoyun; Zhao, Chunling; Bamunuarachchi, Gayan
- Cellular Microbiology, Vol. 21, Issue 5
Quantitative Proteomic Analysis Reveals Unfolded-Protein Response Involved in Severe Fever with Thrombocytopenia Syndrome Virus Infection
journal, May 2019
- Zhang, Lei-Ke; Wang, Bo; Xin, Qilin
- Journal of Virology, Vol. 93, Issue 10
Brucella Downregulates Tumor Necrosis Factor-α to Promote Intracellular Survival via Omp25 Regulation of Different MicroRNAs in Porcine and Murine Macrophages
journal, January 2018
- Luo, Xiaomao; Zhang, Xiujuan; Wu, Xingchen
- Frontiers in Immunology, Vol. 8
Vaccinia virus protein A49 activates Wnt signalling by targetting the E3 ligase β-TrCP
journal, December 2017
- Maluquer de Motes, Carlos; Smith, Geoffrey L.
- Journal of General Virology, Vol. 98, Issue 12