Myocyte enhancer factor (MEF)-2 plays essential roles in T-cell transformation associated with HTLV-1 infection by stabilizing complex between Tax and CREB

Retrovirology

Zafar K Khan³  Edward W Harhaj²  Divya Sagar³  Rashida Ginwala³  Linlin Gao¹  Mohit Sehgal³  Alfonso Lavorgna²  Pooja Jain³ 

[1] Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, The University of Miami, Miller School of Medicine, Miami 33136, FL, USA;Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore 21287, MD, USA;Department of Microbiology & Immunology and Drexel Institute for Biotechnology & Virology Research, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown 18902, PA, USA

关键词: Myocyte enhancer factor-2 (MEF-2);    Retroviral promoter;    LTR;    Tax;    HTLV-1;   

Others  :  1162835
DOI  :  10.1186/s12977-015-0140-1

 received in 2014-04-28, accepted in 2015-01-15,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Jain et al.; licensee BioMed Central.

【 图 表 】

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