The Rex proteins of types I and II human T-cell leukemia viruses (HTLV-I
Background: Activation of telomerase is a critical and late event in tumor progression. Thus, in patients with adult-T cell leukaemia (ATL), an HTLV-1 (Human T cell Leukaemia virus type 1)-associated disease, leukemic cells display a high telomerase activity, mainly through transcriptional up-regulation of the human telomerase catalytic subunit (hTERT). The HBZ (HTLV-1 bZIP) protein coded by the minus strand of HTLV-1 genome and expressed in ATL cells has been shown to increase the transcriptional activity of JunD, an AP-1 protein. The presence of several AP-1 binding sites in the hTERT promoter led us to investigate whether HBZ regulates hTERT gene transcription.
In this report, we analyzed whether the degradation of mRNAs by the nonsense-mediated mRNA decay (NMD) pathway was affected in human T-lymphotropic virus type 1 (HTLV-1)-infected cells. This pathway was indeed strongly inhibited in C91PL, HUT102, and MT2 cells, and such an effect was also observed by the sole expression of the Tax protein in Jurkat and HeLa cells. In line with this activity, Tax binds INT6/EIF3E (here called INT6), which is a subunit of the translation initiation factor eukaryotic initiation factor 3 (eIF3) required for efficient NMD, as well as the NMD core factor upstream frameshift protein 1 (UPF1). It was also observed that Tax expression alters the morphology of processing bodies (P-bodies), the cytoplasmic structures which concentrate RNA degradation factors. The presence of UPF1 in these subcellular compartments was increased by Tax, whereas that of INT6 was decreased. In line with these effects, the level of the phosphorylated form of UPF1 was increased in the presence of Tax. Analysis of several mutants of the viral protein showed that the interaction with INT6 is necessary for NMD inhibition. The alteration of mRNA stability was observed to affect viral transcripts, such as that coding for the HTLV-1 basic leucine zipper factor (HBZ), and also several cellular mRNAs sensitive to the NMD pathway. Our data indicate that the effect of Tax on viral and cellular gene expression is not restricted to transcriptional control but can also involve posttranscriptional regulation. Human T-lymphotropic virus type 1 (HTLV-1) infection is associated with the onset of severe diseases, mainly adult Tcell leukemia (ATL) and tropical spastic paraparesis, also named HTLV-1-associated myelopathy, in 2 to 5% of patients (for a review, see reference 44). These conditions are characterized by a long latency, with infection often occurring in childhood and disease development at an adult age. Accordingly, it is estimated that the development of ATL involves several phases, ending in the acute proliferation of monoclonal ATL cells. At the initial stage, lymphocytes are infected by viral particles, leading to provirus integration and the expression of various viral proteins. Among them, Tax plays an important role both by inducing the transcription of the provirus and by stimulating the proliferation of the host cell. Tax, which is present in both the nucleus and the cytoplasm, exerts these functions by directly binding or by modulating the expression of several key cellular proteins involved in transcriptional control, cell cycle progression, genomic stability, cell adherence and migration, protein degradation, and RNA metabolism (7).Among these various cellular proteins bound by Tax, we have previously characterized INT6, also known as EIF3E, one the 13 subunits of the translation initiation factor eukaryotic initiation factor 3 (eIF3) (16). The complex between both proteins was found to be cytoplasmic, whereas in normal cells, INT6 is present in both the cytoplasm and the nucleus (16,27,64). In mammalian cell...
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