Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%–5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-κB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-κB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-κB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to promote oncogenesis.
Highlights
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and the neurodegenerative disorder HTLV-1 associated myelopathy/tropical spastic paraparesis
TRAF6 was dispensable for Tax to activate IKK in an in vitro system [96], we have found that TRAF6 plays an important role in NF-κB activation in HTLV-1 transformed T cell lines [130]
Tax oncoprotein to hijack the cellular ubiquitin-proteasome machinery to promote aberrant signaling linked to cell survival and proliferation
Summary
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and the neurodegenerative disorder HTLV-1 associated myelopathy/tropical spastic paraparesis. The HTLV-1 genome is flanked by 5' and 3' long terminal repeat (LTR) sequences that contain cis-acting elements that regulate the expression of viral proteins necessary for the virus to infect and replicate in host cells. In addition to regulating viral gene expression, Tax modulates host signaling pathways to induce cell transformation. Tax interacts with specific components of NF-κB pathways to drive the proliferation, survival and transformation of HTLV-1 infected T cells. Phosphorylation of IκB triggers its ubiquitination and proteasomal degradation to liberate NF-κB complexes which concomitantly translocate into the nucleus to bind and activate specific promoters and gene expression. Ubiquitination is a type of PTM, together with phosphorylation, SUMOylation, methylation and glycosylation, that play key regulatory functions for proteins These modifications are essential for all physiological processes in cells, influence the balance between normal and pathogenic cellular signaling and determine the final outcome of viral infections. A common characteristic of DUBs is the presence of ubiquitin-binding domains that bind ubiquitin chains on specific target proteins [84]
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