Abstract
Human T-cell leukemia virus type-1 (HTLV-1) Rex is a viral RNA binding protein. The most important and well-known function of Rex is stabilizing and exporting viral mRNAs from the nucleus, particularly for unspliced/partially-spliced mRNAs encoding the structural proteins essential for viral replication. Without Rex, these unspliced viral mRNAs would otherwise be completely spliced. Therefore, Rex is vital for the translation of structural proteins and the stabilization of viral genomic RNA and, thus, for viral replication. Rex schedules the period of extensive viral replication and suppression to enter latency. Although the importance of Rex in the viral life-cycle is well understood, the underlying molecular mechanism of how Rex achieves its function has not been clarified. For example, how does Rex protect unspliced/partially-spliced viral mRNAs from the host cellular splicing machinery? How does Rex protect viral mRNAs, antigenic to eukaryotic cells, from cellular mRNA surveillance mechanisms? Here we will discuss these mechanisms, which explain the function of Rex as an organizer of HTLV-1 expression based on previously and recently discovered aspects of Rex. We also focus on the potential influence of Rex on the homeostasis of the infected cell and how it can exert its function.
Highlights
Human T-cell leukemia virus type-1 (HTLV-1) Rex is a viral RNA binding protein
By confirming that the genomic and full-length mRNAs of HTLV-1 are sensitive to Nonsense-mediated mRNA decay (NMD), we further demonstrated that Rex inhibited NMD
Accumulating data on the analysis of the Rex interactome shows that Rex has a significantly high potential to interact with a wide variety of cellular proteins
Summary
Infection of T-cells with human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL), HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and HTLV-1 uveitis (HU) [1,2], the molecular basis of such variations in the pathogenesis of HTLV-1 has not been fully elucidated. Tax stimulates the transactivation of LTRs for enhanced tax/rex mRNA transcription Such feed-forward activation of the HTLV-1 provirus results in the gradual accumulation of Rex in the infected cell. The active export of these viral mRNAs to the cytoplasm by Rex results in enhanced translation of the viral structural proteins, Gag, Pro, Pol, and Env and, thereby, enhances viral replication. With the active nuclear-export of unspliced and partially-spliced viral mRNA by Rex, that of tax/rex mRNA is reduced; cellular concentrations of Tax and Rex proteins are decreased. Rex starts exporting the unspliced and partially spliced viral mRNAs, encoding Gag, Pro, Pol, and Env, to the cytoplasm by binding to RxRE of 2viral mRNA (4),resulting in active viral replication (5). Canonical Rex Function as a Post-Transcriptional Regulator of Viral Expression
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