title: Myocyte enhancer factor (MEF)-2 plays essential roles in T-cell transformation associated with HTLV-1 infection by stabilizing complex between Tax and CREB.
abstract: BACKGROUND
  The exact molecular mechanisms regarding HTLV-1 Tax-mediated viral gene expression and CD4 T-cell transformation have yet to be fully delineated. Herein, utilizing virus-infected primary CD4+ T cells and the virus-producing cell line, MT-2, we describe the involvement and regulation of Myocyte enhancer factor-2 (specifically MEF-2A) during the course of HTLV-1 infection and associated disease syndrome.
  
  
  RESULTS
  Inhibition of MEF-2 expression by shRNA and its activity by HDAC9 led to reduced viral replication and T-cell transformation in correlation with a heightened expression of MEF-2 in ATL patients. Mechanistically, MEF-2 was recruited to the viral promoter (LTR, long terminal repeat) in the context of chromatin, and constituted Tax/CREB transcriptional complex via direct binding to the HTLV-1 LTR. Furthermore, an increase in MEF-2 expression was observed upon infection in an extent similar to CREB (known Tax-interacting transcription factor), and HATs (p300, CBP, and p/CAF). Confocal imaging confirmed MEF-2 co-localization with Tax and these proteins were also shown to interact by co-immunoprecipitation. MEF-2 stabilization of Tax/CREB complex was confirmed by a novel promoter-binding assay that highlighted the involvement of NFAT (nuclear factor of activated T cells) in this process via Tax-mediated activation of calcineurin (a calcium-dependent serine-threonine phosphatase). MEF-2-integrated signaling pathways (PI3K/Akt, NF-κB, MAPK, JAK/STAT, and TGF-β) were also activated during HTLV-1 infection of primary CD4+ T cells, possibly regulating MEF-2 activity.
  
  
  CONCLUSIONS
  We demonstrate the involvement of MEF-2 in Tax-mediated LTR activation, viral replication, and T-cell transformation in correlation with its heightened expression in ATL patients through direct binding to DNA within the HTLV-1 LTR.
authors: Pooja
authors: P
authors: Jain
authors: Alfonso
authors: A
authors: Lavorgna
authors: Mohit
authors: M
authors: Sehgal
authors: Linlin
authors: L
authors: Gao
authors: Rashida
authors: R
authors: Ginwala
authors: Divya
authors: D
authors: Sagar
authors: Edward W
authors: EW
authors: Harhaj
authors: Zafar K
authors: ZK
authors: Khan
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000502:physiology / Q000821:virology*; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D016356:Gene Products, tax / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D064326:MEF2 Transcription Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055503:Protein Multimerization; D014158:Transcription, Genetic; D014779:Virus Replication
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016356:Gene Products, tax; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C514970:tax protein, Human T-lymphotrophic virus 1