A CRISPR Activation Screen Identifies an Atypical Rho GTPase That Enhances Zika Viral Entry

A CRISPR Activation Screen Identifies an Atypical Rho GTPase That Enhances Zika Viral Entry

Zika virus (ZIKV) is a re-emerging flavivirus that has caused large-scale epidemics. Infection during pregnancy can lead to neurologic developmental abnormalities in children. There is no approved vaccine or therapy for ZIKV. To uncover cellular pathways required for ZIKV that can be therapeutically...

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Autores principales: Anh Phuong Luu, Zhenlan Yao, Sangeetha Ramachandran, Stephanie A. Azzopardi, Linde A. Miles, William M. Schneider, H.-Heinrich Hoffmann, Leonia Bozzacco, Gustavo Garcia, Danyang Gong, Robert Damoiseaux, Hengli Tang, Kouki Morizono, Charles M. Rudin, Ren Sun, Vaithilingaraja Arumugaswami, John T. Poirier, Margaret R. MacDonald, Charles M. Rice, Melody M. H. Li
Formato: article
Lenguaje:EN
Publicado: MDPI AG 2021
Materias:
CRISPR activation
Zika virus
proviral factors
WWTR1
Rho GTPases
RhoV
Microbiology
QR1-502
Acceso en línea:https://doaj.org/article/2f3d203580654a47b1222b3bf06f5e6f
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Sumario:Zika virus (ZIKV) is a re-emerging flavivirus that has caused large-scale epidemics. Infection during pregnancy can lead to neurologic developmental abnormalities in children. There is no approved vaccine or therapy for ZIKV. To uncover cellular pathways required for ZIKV that can be therapeutically targeted, we transcriptionally upregulated all known human coding genes with an engineered CRISPR–Cas9 activation complex in human fibroblasts deficient in interferon (IFN) signaling. We identified Ras homolog family member V (<i>RhoV</i>) and WW domain-containing transcription regulator 1 (<i>WWTR1</i>) as proviral factors, and found them to play important roles during early ZIKV infection in A549 cells. We then focused on RhoV, a Rho GTPase with atypical terminal sequences and membrane association, and validated its proviral effects on ZIKV infection and virion production in SNB-19 cells. We found that RhoV promotes infection of some flaviviruses and acts at the step of viral entry. Furthermore, RhoV proviral effects depend on the complete GTPase cycle. By depleting Rho GTPases and related proteins, we identified RhoB and Pak1 as additional proviral factors. Taken together, these results highlight the positive role of RhoV in ZIKV infection and confirm CRISPR activation as a relevant method to identify novel host–pathogen interactions.

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