Abstract
The viral Tax oncoprotein plays a key role in both Human T-cell lymphotropic virus type 1 (HTLV-1)-replication and HTLV-1-associated pathologies, notably adult T-cell leukemia. Tax governs the transcription from the viral 5’LTR, enhancing thereby its own expression, via the recruitment of dimers of phosphorylated CREB to cAMP-response elements located within the U3 region (vCRE). In addition to phosphorylation, CREB is also the target of O-GlcNAcylation, another reversible post-translational modification involved in a wide range of diseases, including cancers. O-GlcNAcylation consists in the addition of O-linked-N-acetylglucosamine (O-GlcNAc) on Serine or Threonine residues, a process controlled by two enzymes: O-GlcNAc transferase (OGT), which transfers O-GlcNAc on proteins, and O-GlcNAcase (OGA), which removes it. In this study, we investigated the status of O-GlcNAcylation enzymes in HTLV-1-transformed T cells. We found that OGA mRNA and protein expression levels are increased in HTLV-1-transformed T cells as compared to control T cell lines while OGT expression is unchanged. However, higher OGA production coincides with a reduction in OGA specific activity, showing that HTLV-1-transformed T cells produce high level of a less active form of OGA. Introducing Tax into HEK-293T cells or Tax-negative HTLV-1-transformed TL-om1 T cells is sufficient to inhibit OGA activity and increase total O-GlcNAcylation, without any change in OGT activity. Furthermore, Tax interacts with the OGT/OGA complex and inhibits the activity of OGT-bound OGA. Pharmacological inhibition of OGA increases CREB O-GlcNAcylation as well as HTLV-1-LTR transactivation by Tax and CREB recruitment to the LTR. Moreover, overexpression of wild-type CREB but not a CREB protein mutated on a previously described O-GlcNAcylation site enhances Tax-mediated LTR transactivation. Finally, both OGT and OGA are recruited to the LTR. These findings reveal the interplay between Tax and the O-GlcNAcylation pathway and identify new key molecular actors involved in the assembly of the Tax-dependent transactivation complex.
Highlights
Human T-lymphotropic virus type 1 (HTLV-1) is the only retrovirus associated to a cancer in humans
Human T-cell lymphotropic virus type 1 (HTLV-1) is the only human retrovirus associated to a cancer
We report that Tax interacts with the OGlcNAczyme O-GlcNAc transferase (OGT)/OGA complex that catalyzes O-GlcNAcylation, a post-translational modification often deregulated in cancers
Summary
Human T-lymphotropic virus type 1 (HTLV-1) is the only retrovirus associated to a cancer in humans. HTLV-1 is the etiologic agent of adult T-cell leukemia/lymphoma (ATLL), a very aggressive malignant proliferation of CD4+ T lymphocytes, which appears in 2–5% of infected individuals (reviewed in [1]). The oncogenic power of HTLV-1 is due in large part to the properties of the viral oncoprotein Tax. Tax is a powerful inducer of T-cell proliferation through its ability to activate a broad range of cellular promoters, promote cell cycle and inhibit apoptosis and repair machineries (reviewed in [3]). Tax is critical for HTLV-1 gene expression by virtue of its capacity to transactivate the 5’ LTR that controls the transcription of all HTLV-1 structural, enzymatic and regulatory genes, including Tax itself, and auxiliary genes with the exception of the antisense product HBZ [6]
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