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

Charlotte Vandermeulen, Tina O’Grady, Jerome Wayet, Bartimee Galvan, Sibusiso Maseko, Majid Cherkaoui, Alice Desbuleux, Georges Coppin, Julien Olivet, Lamya Ben Ameur, Keisuke Kataoka, Seishi Ogawa, Olivier Hermine, Ambroise Marcais, Marc Thiry, Franck Mortreux, Michael A. Calderwood, Johan van Weyenbergh, Jean Marie Peloponese, Benoit CharloteauxAnne van den Broeke, David E. Hill, Marc Vidal, Franck Dequiedt, Jean Claude Twizere

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere1009919
JournalPLoS Pathogens
Volume17
Issue number9
DOIs
Publication statusPublished - 2021 Sep
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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