The HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape.

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. Author summary: Tax and HBZ are two viral regulatory proteins encoded by the human T-cell leukemia virus type 1 (HTLV-1) via sense and antisense transcripts, respectively. Both proteins are known to drive oncogenic processes that culminate in a T-cell neoplasm, known as Adult T cell leukemia/lymphoma (ATLL). We measured the effects of Tax and HBZ on host gene expression pathway by analyzing the interactome with cellular transcriptional and post-transcriptional regulators, and the transcriptome and mRNA splicing of cell lines expressing either Tax or HBZ. We compared our results with data obtained from independent cohorts of Japanese and Afro-Caribbean patients, and identified common splicing changes that might represent clinically useful biomarkers for ATLL. Finally, we provide evidence that the viral protein Tax can reprogram initial steps of the T-cell transcriptome diversification by hijacking the U2AF complex, a key cellular regulator of pre-mRNA splicing. [ABSTRACT FROM AUTHOR]