Open AccessThe HTLV-1 viral oncoproteins Tax and HBZ reprogram the cellular mRNA splicing landscape
Author(s) -
Charlotte Vandermeulen,
Tina O’Grady,
Jérôme Wayet,
Bartimée Galvan,
Sibusiso B. Maseko,
Majid Cherkaoui,
Alice Desbuleux,
Georges Coppin,
Julien Olivet,
Lydia Ameur,
Keisuke Kataoka,
Seishi Ogawa,
Olivier Hermine,
Ambroise Marçais,
Marc Thiry,
Franck Mortreux,
Michael A. Calderwood,
Johan Van Weyenbergh,
Jean Marie Peloponese,
Benoît Charloteaux,
Anne Van den Broeke,
David E. Hill,
Marc Vidal,
Samuel Dequiedt,
Jean-Claude Twizere
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009919
Subject(s) - interactome , biology , rna splicing , exon , alternative splicing , transcriptome , microbiology and biotechnology , transcription (linguistics) , spliceosome , transcription factor , genetics , computational biology , rna , gene , gene expression , linguistics , philosophy
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.