Abstract
BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis. HTLV-1 encodes transactivator protein Tax that interacts with various cellular factors to modulate transcription and other biological functions. Additional cellular mediators of Tax-mediated transcriptional activation of HTLV-1 long terminal repeats (LTR) remain to be identified and characterized.ResultsIn this study, we investigated the regulatory role of group I p21-activated kinases (Paks) in Tax-induced LTR activation. Both wild-type and kinase-dead mutants of Pak3 were capable of potentiating the activity of Tax to activate LTR transcription. The effect of Paks on the LTR was attributed to the N-terminal regulatory domain and required the action of CREB, CREB-regulating transcriptional coactivators (CRTCs) and p300/CREB-binding protein. Paks physically associated with Tax and CRTCs. Paks were recruited to the LTR in the presence of Tax. siRNAs against either Pak1 or Pak3 prevented the interaction of Tax with CRTC1 and the recruitment of Tax to the LTR. These siRNAs also inhibited LTR-dependent transcription in HTLV-1-transformed MT4 cells and in cells transfected with an infectious clone of HTLV-1.ConclusionGroup I Paks augment Tax-mediated transcriptional activation of HTLV-1 LTR in a kinase-independent manner.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis
Augmentation of Tax-induced activation of HTLV-1 long terminal repeats (LTR) by group I p21-activated kinases (Paks) p21-activated kinase 3 (Pak3) is known to interact with Tax in HTLV-1-transformed cells [18]
We set out to explore whether Pak1, Pak2 and Pak3 might affect Tax-induced activation of HTLV-1 LTR
Summary
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia and tropical spastic paraparesis. Additional cellular mediators of Tax-mediated transcriptional activation of HTLV-1 long terminal repeats (LTR) remain to be identified and characterized. Human T-cell leukemia virus type 1 (HTLV-1) infects more than 20 million people worldwide and causes adult T-cell leukemia (ATL) or tropical spastic paraparesis (TSP) in a small subset of infected individuals. The master regulator of HTLV-1 proviral expression is viral transactivator Tax which potently activates transcription from the long terminal repeats (LTR). For this activation, Tax forms a dimer to complex with dimeric CREB and the three imperfectly conserved Tax-responsive elements (TREs) in the LTR [3,4,5]. It will be of great interest to see whether any Tax-binding protein kinases would play a role in this process
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