Journal
VIRUSES-BASEL
Volume 13, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/v13112113
Keywords
CRISPR activation; Zika virus; proviral factors; WWTR1; Rho GTPases; RhoV
Categories
Funding
- UCLA Clinical and Translational Science Institute Core Voucher Award
- UCLA Jonsson Comprehensive Cancer Center (JCCC) Seed Grant
- UC Cancer Research Coordinating Committee Faculty Seed Grant [CRN-20-637544]
- National Institute of Health (NIH) [R01AI158704, R01AI091707, P01AI138938, P30 CA008748]
- Robertson Foundation
- Lung Cancer Research Foundation
- NIH [R01AI145044, U19AI149504]
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In the study, RhoV and WWTR1 were identified as important factors in early Zika virus infection, with RhoV playing a significant role in promoting viral infection and production. Additionally, RhoV was found to facilitate infection of certain flaviviruses and act at the viral entry step.
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 (RhoV) and WW domain-containing transcription regulator 1 (WWTR1) 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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