Model explaining MEF-2 activity on Tax-mediated transactivation of HTLV-1 LTR. Type II HDACs (HDAC4/5/7/9) bind to MEF-2A and repress its transcriptional activity. Upon HTLV-1 infection, Tax activates p38 and ERK5, which phosphorylate MEF-2 leading to its dissociation from the MEF-2A: HDAC repressive complex. On the other hand, Tax also binds to Smad2/3/4 to prevent their constitutive binding to transcription co-activators CBP/p300. This leads to increased availability of CBP/p300 to bind Tax/pCREB complex bound to the 5′ LTR region of the provirus. Along with Tax/pCREB/CBP/p300 complex, recruitment of MEF-2A to the 5′ LTR promotes viral gene expression. Tax also activates Calcineurin (a calcium-dependent serine-threonine phosphatase), which dephosphorylates NFAT. Upon dephosphorylation, NFAT translocates to nucleus and is recruited to the HTLV-1 5′ LTR along with the Tax/pCREB/CBP/p300 complex. NFAT is also recruited to the MEF-2A gene promoter where it binds to MEF-2A and turns on transcription resulting in upregulation of MEF-2A expression. HDAC, Histone deacetylase; MEF-2A, Myocyte-specific enhancer factor 2A; ERK5, Extracellular-signal-regulated kinase 5; Smad, Sma- and Mad-Related Protein; CREB, cAMP response element-binding protein; CBP, CREB-binding protein; NFAT, Nuclear factor of activated T cells.