Abstract
Viral infections are known to hijack the transcription and translation of the host cell. However, the extent to which viral proteins coordinate these perturbations remains unclear. Here we used a model system, the human T-cell leukemia virus type 1 (HTLV-1), and systematically analyzed the transcriptome and interactome of key effectors oncoviral proteins Tax and HBZ. We showed that Tax and HBZ target distinct but also common transcription factors. Unexpectedly, we also uncovered a large set of interactions with RNA-binding proteins, including the U2 auxiliary factor large subunit (U2AF2), a key cellular regulator of pre-mRNA splicing. We discovered that Tax and HBZ perturb the splicing landscape by altering cassette exons in opposing manners, with Tax inducing exon inclusion while HBZ induces exon exclusion. Among Tax- and HBZ-dependent splicing changes, we identify events that are also altered in Adult T cell leukemia/lymphoma (ATLL) samples from two independent patient cohorts, and in well-known cancer census genes. Our interactome mapping approach, applicable to other viral oncogenes, has identified spliceosome perturbation as a novel mechanism coordinated by Tax and HBZ to reprogram the transcriptome.
Highlights
The ability of a retrovirus to transform its host cell was originally attributed to integration of retroviral DNA into the host cell’s genome
Previous studies have shown that Tax and HBZ viral proteins control viral gene expression by competing for binding to key transcriptional factors of the CREB/ATF pathway, and coactivators CBP and p300 (S1A and S1B Fig), complexes that are targeted by other viral oncoproteins including high-risk human papillomavirus (HPV) E6 proteins [23]
We aimed at providing an unbiased map of protein-protein interactions (PPIs) established by Tax and HBZ viral oncoproteins with cellular gene expression regulators, including transcription factors (TFs) and RNA-binding proteins (RBPs) (S1C Fig)
Summary
The ability of a retrovirus to transform its host cell was originally attributed to integration of retroviral DNA into the host cell’s genome. This integration allowed the discovery of cellular oncogenes and related cellular signaling pathways such as the SRC [1], EGFR [2] MYC [3] RAS [4], and PI3K pathways [5]. No universal model has been developed to explain oncogenic transformation as a phenotypic result of retroviral integration. Proviral integration sites for HTLV-1 are enriched in cancer driver genes, resulting in altered transcription of those genes [8]. The key initial drivers of ATLL are the viral proteins Tax and HBZ, which can independently induce leukemia in transgenic mouse models [9,10]
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