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

Cui, Xiaoxu LU ; Hao, Chengyu LU ; Gong, Lijing LU ; Kajitani, Naoko LU and Schwartz, Stefan LU (2022) In Nucleic Acids Research 50(5). p.2782-2806
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... (More)

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.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
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
in
Nucleic Acids Research
volume
50
issue
5
pages
2782 - 2806
publisher
Oxford University Press
external identifiers
  • scopus:85127584258
  • pmid:35234917
ISSN
1362-4962
DOI
10.1093/nar/gkac132
language
English
LU publication?
yes
additional info
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
id
7c00f4e7-3751-4453-9274-272269cfb2ad
date added to LUP
2022-05-08 10:53:42
date last changed
2024-06-09 11:54:15
@article{7c00f4e7-3751-4453-9274-272269cfb2ad,
  abstract     = {{<p>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.</p>}},
  author       = {{Cui, Xiaoxu and Hao, Chengyu and Gong, Lijing and Kajitani, Naoko and Schwartz, Stefan}},
  issn         = {{1362-4962}},
  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}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{2782--2806}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{HnRNP D activates production of HPV16 E1 and E6 mRNAs by promoting intron retention}},
  url          = {{http://dx.doi.org/10.1093/nar/gkac132}},
  doi          = {{10.1093/nar/gkac132}},
  volume       = {{50}},
  year         = {{2022}},
}