Abstract
BackgroundIn contrast with human T-cell leukemia virus type 1 (HTLV-1) that causes ATL (adult T-cell leukemia), HTLV-2 has not been causally linked to malignant disease. The minus strand of the HTLV genomes encode the regulatory proteins HTLV-1 bZIP factor (HBZ) for HTLV-1 and antisense protein of HTLV-2 (APH-2) for HTLV-2. Unlike the viral proteins Tax1 and Tax2, both HBZ and APH-2 are constitutively expressed in infected cells suggesting that they may play important roles in the pathogenesis of these viruses. To date, very little is known about the function of APH-2 except that it inhibits Tax2-mediated transcription of HTLV-2 genes. In the present study, we investigated the role of APH-2 in basal and Tax2B-mediated activation of the AP-1 pathway.ResultsWe demonstrate that, unlike HBZ, APH-2 stimulates basal AP-1 transcription by interacting with c-Jun and JunB through its non-conventional bZIP domain. In addition, when Tax2 and APH-2 are co-expressed, they physically interact in vivo and in vitro and APH-2 acts as an inhibitor of Tax2-mediated activation of AP-1 transcription.ConclusionsThis report is the first to document that HTLV-2 can modulate the AP-1 pathway. Altogether our results reveal that, in contrast with HBZ, APH-2 regulates AP-1 activity in a Tax2-dependant manner. As the AP-1 pathway is involved in numerous cellular functions susceptible to affect the life cycle of the virus, these distinct biological properties between HBZ and APH-2 may contribute to the differential pathogenic potential of HTLV-1 and HTLV-2.
Highlights
In contrast with human T-cell leukemia virus type 1 (HTLV-1) that causes adult T-cell leukemia (ATL), HTLV-2 has not been causally linked to malignant disease
antisense protein of HTLV-2 (APH-2) stimulates the transcriptional activity of c-Jun, JunB and JunD In order to investigate the effect of APH-2 on basal AP1 transcription compared to HTLV-1 bZIP factor (HBZ), we performed luciferase assays using an AP-1 cis-reporter plasmid that contains the luciferase reporter gene driven by a basic promoter element plus seven repeats of AP-1 binding sites
FLAG-APH-2ΔbZIP was present in the immunoprecipitate, confirming that APH-2 and Tax2B interact in vivo but not through the non-conventional bZIP domain of APH-2 (Figure 6B, with the indicated antibodies (WB) anti-FLAG, columns 4–6). These results reveal that c-Jun and JunB, but not Tax2B, interact with APH-2 though its nonconventional bZIP domain, which is consistent with our data showing that c-Jun/JunB and Tax2B do not compete for APH-2
Summary
In contrast with human T-cell leukemia virus type 1 (HTLV-1) that causes ATL (adult T-cell leukemia), HTLV-2 has not been causally linked to malignant disease. The HTLV-1 Tax protein is a transcriptional activator that regulates HTLV-1 gene expression and modulates the expression of numerous cellular genes through activation of cellular transcription factors including NF-κB [11], CREB [12,13,14,15,16], SRF [17] and AP-1 [18]. Activation of these major cellular signal transduction pathways plays a critical role in T-cell transformation, and ATL development. HTLV-1 Tax up-regulates the transcription of several AP-1 family members such as c-Jun, JunD, c-Fos and Fra-1 [20,21]
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