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

PLoS Pathog. 2021 Sep 20;17(9):e1009919. doi: 10.1371/journal.ppat.1009919. eCollection 2021 Sep.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Gene Products, tax / metabolism*
  • HEK293 Cells
  • HTLV-I Infections / etiology
  • HTLV-I Infections / metabolism*
  • Human T-lymphotropic virus 1
  • Humans
  • Jurkat Cells
  • Leukemia-Lymphoma, Adult T-Cell / virology*
  • RNA Splicing
  • RNA, Messenger
  • Retroviridae Proteins / metabolism*
  • Splicing Factor U2AF / metabolism


  • Basic-Leucine Zipper Transcription Factors
  • Gene Products, tax
  • HBZ protein, human T-cell leukemia virus type I
  • RNA, Messenger
  • Retroviridae Proteins
  • Splicing Factor U2AF
  • U2AF2 protein, human
  • tax protein, Human T-lymphotrophic virus 1