Mechanisms of Oncogenesis by HTLV-1 Tax

Abstract

The human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), a neoplasm of CD4+CD25+ T cells that occurs in 2-5% of infected individuals after decades of asymptomatic latent infection. Multiple HTLV-1-encoded regulatory proteins, including Tax and HTLV-1 basic leucine zipper factor (HBZ), play key roles in viral persistence and latency. The HTLV-1 Tax oncoprotein interacts with a plethora of host cellular proteins to regulate viral gene expression and also promote the aberrant activation of signaling pathways such as NF-κB to drive clonal proliferation and survival of T cells bearing the HTLV-1 provirus. Tax undergoes various post-translational modifications such as phosphorylation and ubiquitination that regulate its function and subcellular localization. Tax shuttles in different subcellular compartments for the activation of anti-apoptotic genes and deregulates the cell cycle with the induction of DNA damage for the accumulation of genomic instability that can result in cellular immortalization and malignant transformation. However, Tax is highly immunogenic and therefore HTLV-1 has evolved numerous strategies to tightly regulate Tax expression while maintaining the pool of anti-apoptotic genes through HBZ. In this review, we summarize the key findings on the oncogenic mechanisms used by Tax that set the stage for the development of ATLL, and the strategies used by HTLV-1 to tightly regulate Tax expression for immune evasion and viral persistence.

Keywords: ATLL; HTLV-1; NF-κB; Tax; apoptosis.

Figure 1

Tax activation of canonical and noncanonical NF-κB signaling. Tax interacts with ring finger protein 8 (RNF8) and linear ubiquitin assembly complex (LUBAC) to recruit K63-linked polyubiquitin chains and linear ubiquitin chains, respectively, to induce IκB kinase (IKK) activation. Tax also interacts with IκBα and p105 to disrupt NF-κB/IκB complexes with subsequent phosphorylation and proteasomal degradation of IκBα and processing to p50, respectively. Tax interacts with and promotes the nuclear translocation of active NF-κB dimers to enhance DNA binding and transcriptional activity. Tax also activates noncanonical NF-κB signaling through interaction with IκB kinase α (IKKα) and NF-κB essential modulator (NEMO) to induce the proteasomal processing of p100 to active p52 and trigger its nuclear translocation along with RelB to activate NF-κB target genes. Tax also interacts with TAX1BP1 to disrupt the Itch, RNF11, NRP and A20 complex to potentiate and sustain NF-κB activation. Cell adhesion molecule 1 (CADM1) interaction with Tax also facilitates Ubc13-mediated K63-linked polyubiquitination of Tax and NF-κB activation. Tax interacts with HSP90 for protection against proteasomal degradation mediated by PDLIM2-triggered K48-linked polyubiquitination in the nuclear matrix. Tax is also monoubiquitinated upon genotoxic stress to trigger its nuclear export in a CRM-1-dependent manner. SUMOylation of Tax is mediated by Ubc9 and SUMOylated Tax is found in nuclear bodies. Acetylated Tax also interacts with p300 in the nucleus. Tax interacts with TRAF6 to stabilize MCL-1 through K63-linked polyubiquitination in mitochondria, and its interaction with USP10 leads to increased reactive oxygen species (ROS) production to inhibit apoptosis. Tax also interacts with CREB-activating transcription factor family protein (CREB/ATF) and recruits CBP/300 to the long terminal repeat (LTR) for trans-activation of the viral promoter. The NF-κB canonical pathway is indicated by solid black lines with arrows. The noncanonical NF-κB pathway is indicated by solid red lines with arrows.

Figure 2

Tax induction of DNA damage, deregulation of the cell cycle, inhibition of apoptosis, and modulation of miRNA expression. Upon DNA damage, Tax suppresses ataxia-telangiectasia mutated (ATM) kinase activation and mediator of DNA damage checkpoint 1 (MDC1) to increase genomic instability with subsequent impairment of homologous recombination, and inhibits mismatch repair (MMR) regulatory genes to block mismatch repair to induce DNA damage. Additionally, Tax increases proliferating cell nuclear antigen (PCNA) expression to overcome the p21^waf1/cip1-mediated replication block to sustain DNA replication with increased mutation frequency for the accumulation of genomic instability. Tax deregulates the cell cycle and transcribes S phase genes through the hyperphosphorylation of Rb and enhances WIP1 phosphatase activity with concomitant inhibition of CDK4 inhibitors such as p15, p16, p18 and p19, and tumor suppressor p53. Tax also facilitates M phase transition by the activation of anaphase-promoting complex (APC) and its binding partner cdc20 and induces centrosome amplification to trigger aneuploidy. Tax inhibits apoptosis by enhancing the expression of anti-apoptotic proteins such as X-linked inhibitor of apoptosis (XIAP), survivin, BCL-2, Bcl-xL, Bfl-1/A1 and cFLIP and impairs caspase signaling by inactivation of caspase-3, -7, -8 and -9. Tax also stabilizes anti-apoptotic MCL-1 through K63-linked polyubiquitination. Tax promotes functional inactivation of p53 through its phosphorylation and induces expression of Ras proteins and cyclic AMP (cAMP) to augment cell proliferation with increased metabolism. Tax also modulates miRNA expression to fine-tune gene expression for cellular transformation. Tax upregulates miR-146a, miR-130b and miR-155, and downregulates miR-149, miR-135b, miR-872 and miR-873 to promote the proliferation of infected T cells.

Figure 3

Regulation of Tax expression by viral and cellular mechanisms. The CD8+ T cells specific for Tax antigens are impaired by activated Tregs via the secretion of IL-10 through Tax-mediated NF-κB activation. However, levels of IL-10 are maintained by a positive feedback loop of signal transducer and activator of transcription 3 (STAT3) to maintain the pool of anti-apoptotic genes even in the absence of Tax. As Tax is highly immunogenic, human T-cell lymphotropic virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) suppresses Tax-mediated transcription (1), and HTLV-1 p30 (2) also blocks Tax trans-activation of the viral LTR by competitive binding to CBP/300 and sequestering doubly spliced viral RNA in the nucleus. However, Tax expression can be induced by hypoxia and oxidative stress. In Tax-negative cells, HBZ is constitutively expressed, and chronic activation of NF-κB signaling is maintained by aberrant expression of NF-κB-inducing kinase (NIK) to transcribe anti-apoptotic genes for sustained lymphoproliferation. It is also possible that activated interferon-stimulated genes (ISGs)/pattern recognition receptors (PRRs) triggered by sensing of anti-sense RNA containing the HTLV-1 LTR may contribute to NF-κB activation.