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Gem-induced cytoskeleton remodeling increases cellular migration of HTLV-1-infected cells, formation of infected-to-target T-cell conjugates and viral transmission
- Source :
- PLoS Pathogens, PLoS Pathogens, Public Library of Science, 2014, 10 (2), pp.1003917. ⟨10.1371/journal.ppat.1003917⟩, PLoS Pathogens, Vol 10, Iss 2, p e1003917 (2014), PLoS Pathogens, 2014, 10 (2), pp.1003917. ⟨10.1371/journal.ppat.1003917⟩
- Publication Year :
- 2013
-
Abstract
- Efficient HTLV-1 viral transmission occurs through cell-to-cell contacts. The Tax viral transcriptional activator protein facilitates this process. Using a comparative transcriptomic analysis, we recently identified a series of genes up-regulated in HTLV-1 Tax expressing T-lymphocytes. We focused our attention towards genes that are important for cytoskeleton dynamic and thus may possibly modulate cell-to-cell contacts. We first demonstrate that Gem, a member of the small GTP-binding proteins within the Ras superfamily, is expressed both at the RNA and protein levels in Tax-expressing cells and in HTLV-1-infected cell lines. Using a series of ChIP assays, we show that Tax recruits CREB and CREB Binding Protein (CBP) onto a c-AMP Responsive Element (CRE) present in the gem promoter. This CRE sequence is required to drive Tax-activated gem transcription. Since Gem is involved in cytoskeleton remodeling, we investigated its role in infected cells motility. We show that Gem co-localizes with F-actin and is involved both in T-cell spontaneous cell migration as well as chemotaxis in the presence of SDF-1/CXCL12. Importantly, gem knock-down in HTLV-1-infected cells decreases cell migration and conjugate formation. Finally, we demonstrate that Gem plays an important role in cell-to-cell viral transmission.<br />Author Summary HTLV-1 was the first human oncoretrovirus to be discovered. Five to ten million people are infected, and 1–6% will develop either Adult T-cell Leukemia, or Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (TSP/HAM). HTLV-1 infects primarily T-cells, but dendritic cells were also found to carry proviruses. Contrary to HIV-1, cell-free HTLV-1 viral particles are poorly infectious. Thus, efficient viral transmission relies on formation of virological synapses or formation and transfer of viral biofilm-like structures. The Tax viral transactivator plays a key role in both modes of transmission. Using transcriptomic analyses, we recently identified cellular genes that are deregulated following Tax expression in T-cells. We focused our attention on genes that are important for cell architecture and are thus likely to modulate cell-to-cell contacts and motility. We found that Gem was highly upregulated both at the RNA and protein levels in Tax-expressing cells and HTLV-1-infected cell lines. We further show that Tax binds cellular co-activators and transcription factor and activates transcription from the gem promoter. We demonstrated that Gem is involved in cellular migration of HTLV-1-infected cells. Importantly, gem knockdown decreases the rate of HTLV-1-infected cell migration and cell-to-cell conjugate formation. We also show that Gem plays an important role in HTLV-1 transmission through cell-to-cell contacts, the most efficient mode of viral infection.
- Subjects :
- endocrine system diseases
T-Lymphocytes
Fluorescent Antibody Technique
Gene Expression
[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
0302 clinical medicine
1108 Medical Microbiology
Transduction, Genetic
[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
Molecular Cell Biology
Biology (General)
Cytoskeleton
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology
0303 health sciences
Human T-lymphotropic virus 1
biology
Reverse Transcriptase Polymerase Chain Reaction
Cell migration
Gene Products, tax
3. Good health
Chemotaxis, Leukocyte
medicine.anatomical_structure
1107 Immunology
030220 oncology & carcinogenesis
[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
0605 Microbiology
Research Article
Gene Expression Regulation, Viral
Transcriptional Activation
Chromatin Immunoprecipitation
QH301-705.5
T cell
Immunology
Immunoblotting
CREB
Microbiology
Virus transmission
Cell Line
03 medical and health sciences
Virology
Genetics
medicine
CREB-binding protein
Molecular Biology
Biology
Actin
030304 developmental biology
Monomeric GTP-Binding Proteins
HEK 293 cells
RC581-607
Molecular biology
HTLV-1
Cell culture
Viruses and Cancer
biology.protein
Parasitology
Immunologic diseases. Allergy
Viral Transmission and Infection
Subjects
Details
- ISSN :
- 15537374 and 15537366
- Volume :
- 10
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- PLoS pathogens
- Accession number :
- edsair.doi.dedup.....6cd8a5eba6cdfbe177658fd19e35bc85