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Zika virus non-structural protein NS4A restricts eye growth in Drosophila through regulation of JAK/STAT signaling.
- Source :
-
Disease models & mechanisms [Dis Model Mech] 2020 Apr 30; Vol. 13 (4). Date of Electronic Publication: 2020 Apr 30. - Publication Year :
- 2020
-
Abstract
- To gain a comprehensive view of the changes in host gene expression underlying Zika virus (ZIKV) pathogenesis, we performed whole-genome RNA sequencing (RNA-seq) of ZIKV-infected Drosophila adult flies. RNA-seq analysis revealed that ZIKV infection alters several and diverse biological processes, including stress, locomotion, lipid metabolism, imaginal disc morphogenesis and regulation of JAK/STAT signaling. To explore the interaction between ZIKV infection and JAK/STAT signaling regulation, we generated genetic constructs overexpressing ZIKV-specific non-structural proteins NS2A, NS2B, NS4A and NS4B. We found that ectopic expression of non-structural proteins in the developing Drosophila eye significantly restricts growth of the larval and adult eye and correlates with considerable repression of the in vivo JAK/STAT reporter, 10XStat92E-GFP At the cellular level, eye growth defects are associated with reduced rate of proliferation without affecting the overall rate of apoptosis. In addition, ZIKV NS4A genetically interacts with the JAK/STAT signaling components; co-expression of NS4A along with the dominant-negative form of domeless or StatRNAi results in aggravated reduction in eye size, while co-expression of NS4A in HopTuml (also known as hop <superscript>Tum</superscript> ) mutant background partially rescues the h o p -induced eye overgrowth phenotype. The function of ZIKV NS4A in regulating growth is maintained in the wing, where ZIKV NS4A overexpression in the pouch domain results in reduced growth linked with diminished expression of Notch targets, Wingless (Wg) and Cut, and the Notch reporter, NRE-GFP Thus, our study provides evidence that ZIKV infection in Drosophila results in restricted growth of the developing eye and wing, wherein eye phenotype is induced through regulation of JAK/STAT signaling, whereas restricted wing growth is induced through regulation of Notch signaling. The interaction of ZIKV non-structural proteins with the conserved host signaling pathways further advance our understanding of ZIKV-induced pathogenesis.This article has an associated First Person interview with the first author of the paper.<br />Competing Interests: Competing interestsThe authors declare no competing or financial interests.<br /> (© 2020. Published by The Company of Biologists Ltd.)
- Subjects :
- Animals
Apoptosis
Cell Proliferation
Down-Regulation genetics
Drosophila melanogaster genetics
Epithelium growth & development
Eye cytology
Gene Expression Profiling
Gene Expression Regulation, Developmental
Larva growth & development
Organ Size
Phenotype
Receptors, Notch metabolism
Reproducibility of Results
Transcriptome genetics
Transgenes
Up-Regulation genetics
Veins growth & development
Wings, Animal growth & development
Zika Virus Infection genetics
Zika Virus Infection virology
Drosophila Proteins metabolism
Drosophila melanogaster virology
Eye growth & development
Janus Kinases metabolism
STAT Transcription Factors metabolism
Signal Transduction
Viral Nonstructural Proteins metabolism
Zika Virus metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1754-8411
- Volume :
- 13
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Disease models & mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 32152180
- Full Text :
- https://doi.org/10.1242/dmm.040816