HnRNP D activates production of HPV16 E1 and E6 mRNAs by promoting intron retention

Xiaoxu Cui, Chengyu Hao, Lijing Gong, Naoko Kajitani, Stefan Schwartz

Research output: Contribution to journalArticlepeer-review

Abstract

Human papillomavirus type 16 (HPV16) E1 and E6 proteins are produced from mRNAs with retained introns, but it has been unclear how these mRNAs are generated. Here, we report that hnRNP D act as a splicing inhibitor of HPV16 E1/E2- and E6/E7-mRNAs thereby generating intron-containing E1- and E6-mRNAs, respectively. N- and C-termini of hnRNP D contributed to HPV16 mRNA splicing control differently. HnRNP D interacted with the components of splicing machinery and with HPV16 RNA to exert its inhibitory function. As a result, the cytoplasmic levels of intron-retained HPV16 mRNAs were increased in the presence of hnRNP D. Association of hnRNP D with HPV16 mRNAs in the cytoplasm was observed, and this may correlate with unexpected inhibition of HPV16 E1- and E6-mRNA translation. Notably, hnRNP D40 interacted with HPV16 mRNAs in an HPV16-driven tonsillar cancer cell line and in HPV16-immortalized human keratinocytes. Furthermore, knockdown of hnRNP D in HPV16-driven cervical cancer cells enhanced production of the HPV16 E7 oncoprotein. Our results suggest that hnRNP D plays significant roles in the regulation of HPV gene expression and HPV-associated cancer development.

Original languageEnglish
Pages (from-to)2782-2806
JournalNucleic Acids Research
Volume50
Issue number5
DOIs
Publication statusPublished - 2022

Subject classification (UKÄ)

  • Microbiology in the medical area
  • Cancer and Oncology

Free keywords

  • Female
  • Human papillomavirus 16/genetics
  • Humans
  • Introns/genetics
  • Oncogene Proteins, Viral/metabolism
  • Papillomavirus Infections/genetics
  • RNA, Messenger/genetics
  • Repressor Proteins/metabolism
  • Uterine Cervical Neoplasms/genetics

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