Hippo signaling effectors YAP and TAZ induce Epstein-Barr Virus (EBV) lytic reactivation through TEADs in epithelial cells

Autor: Makoto Ohashi, Nicholas P. Pauly, Jillian A. Bristol, Nicholas Van Sciver, Shannon C. Kenney, Scott E. Nelson, Eric Johannsen
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Keratinocytes
Small interfering RNA
Epstein-Barr Virus Infections
Herpesvirus 4
Human
B Cells
Cellular differentiation
Cell Cycle Proteins
medicine.disease_cause
Biochemistry
Epithelium
White Blood Cells
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
Post-Translational Modification
Phosphorylation
Biology (General)
0303 health sciences
B-Lymphocytes
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
TEA Domain Transcription Factors
Cell Differentiation
Transfection
Virus Latency
DNA-Binding Proteins
Nucleic acids
Lytic cycle
Hippo signaling
030220 oncology & carcinogenesis
Host-Pathogen Interactions
Cellular Types
Anatomy
Research Article
QH301-705.5
Immune Cells
Immunology
Biology
Protein Serine-Threonine Kinases
Research and Analysis Methods
Microbiology
03 medical and health sciences
Tubulins
Virology
medicine
Genetics
Humans
Hippo Signaling Pathway
Molecular Biology Techniques
Non-coding RNA
Antibody-Producing Cells
Molecular Biology
030304 developmental biology
Blood Cells
Activator (genetics)
Biology and Life Sciences
Proteins
Epithelial Cells
Cell Biology
RC581-607
Epstein–Barr virus
Viral Replication
BZLF1
Gene regulation
Cytoskeletal Proteins
Biological Tissue
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Cancer research
RNA
Parasitology
Virus Activation
Gene expression
Immunologic diseases. Allergy
Transcription Factors
Developmental Biology
Zdroj: PLoS Pathogens, Vol 17, Iss 8, p e1009783 (2021)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: The Epstein-Barr virus (EBV) human herpesvirus is associated with B-cell and epithelial-cell malignancies, and both the latent and lytic forms of viral infection contribute to the development of EBV-associated tumors. Here we show that the Hippo signaling effectors, YAP and TAZ, promote lytic EBV reactivation in epithelial cells. The transcriptional co-activators YAP/TAZ (which are inhibited by Hippo signaling) interact with DNA-binding proteins, particularly TEADs, to induce transcription. We demonstrate that depletion of either YAP or TAZ inhibits the ability of phorbol ester (TPA) treatment, cellular differentiation or the EBV BRLF1 immediate-early (IE) protein to induce lytic EBV reactivation in oral keratinocytes, and show that over-expression of constitutively active forms of YAP and TAZ reactivate lytic EBV infection in conjunction with TEAD family members. Mechanistically, we find that YAP and TAZ interact with, and activate, the EBV BZLF1 immediate-early promoter. Furthermore, we demonstrate that YAP, TAZ, and TEAD family members are expressed at much higher levels in epithelial cell lines in comparison to B-cell lines, and find that EBV infection of oral keratinocytes increases the level of activated (dephosphorylated) YAP and TAZ. Finally, we have discovered that lysophosphatidic acid (LPA), a known YAP/TAZ activator that plays an important role in inflammation, induces EBV lytic reactivation in epithelial cells through a YAP/TAZ dependent mechanism. Together these results establish that YAP/TAZ are powerful inducers of the lytic form of EBV infection and suggest that the ability of EBV to enter latency in B cells at least partially reflects the extremely low levels of YAP/TAZ and TEADs in this cell type.
Author summary EBV causes infectious mononucleosis and persists in latently infected B cells for life. The virus periodically reactivates to a lytic form that produces infectious virus particles, allowing the virus to infect new cells and be transmitted to new hosts. Oral epithelial cells are an important site of lytic viral infection, promoting secretion of infectious virus into saliva. Rarely, EBV infection results in B-cell and epithelial-cell human tumors, and both the latent and lytic forms of infection contribute to these malignancies. However, the viral and cellular factors that determine whether the virus remains latent or lytic are still incompletely understood. Here we have discovered that the Hippo signaling pathway is an important regulator of lytic EBV reactivation, particularly in epithelial cells. We show that transcriptional co-activators YAP and TAZ (which are turned off by Hippo signaling) are strong inducers of lytic EBV reactivation, collaborating with DNA-binding TEAD proteins to activate EBV immediate-early genes. Furthermore, we demonstrate that epithelial cells express much higher levels of YAP/TAZ/TEADs in comparison to B cells, helping to explain why B cells support latent infection. Finally, we find that lysophosphatidic acid, a YAP/TAZ activator, induces lytic reactivation through a YAP/TAZ-dependent mechanism.
Databáze: OpenAIRE
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