Gem-induced cytoskeleton remodeling increases cellular migration of HTLV-1-infected cells, formation of infected-to-target T-cell conjugates and viral transmission

PLoS Pathog. 2014 Feb 27;10(2):e1003917. doi: 10.1371/journal.ppat.1003917. eCollection 2014 Feb.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chemotaxis, Leukocyte / physiology
  • Chromatin Immunoprecipitation
  • Cytoskeleton / metabolism*
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Viral / physiology
  • Gene Products, tax / metabolism
  • Human T-lymphotropic virus 1*
  • Immunoblotting
  • Monomeric GTP-Binding Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology
  • T-Lymphocytes / virology*
  • Transcriptional Activation / physiology
  • Transduction, Genetic

Substances

  • Gene Products, tax
  • GEM protein, human
  • Monomeric GTP-Binding Proteins

Grants and funding

RM and AC are supported by Ecole Normale Supérieure de Lyon. SAC was supported by Fondation pour la Recherche Médicale and InCa (Cancéropôle CLARA). JT was supported by FONDATION ARC. The authors acknowledge the support of Association de Recherche sur le Cancer and of La Ligue Contre le Cancer (équipe Labellisée). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.