title: Suppression of HPV-16 late L1 5'-splice site SD3632 by binding of hnRNP D proteins and hnRNP A2/B1 to upstream AUAGUA RNA motifs.
abstract: Human papillomavirus type 16 (HPV-16) 5'-splice site SD3632 is used exclusively to produce late L1 mRNAs. We identified a 34-nt splicing inhibitory element located immediately upstream of HPV-16 late 5'-splice site SD3632. Two AUAGUA motifs located in these 34 nt inhibited SD3632. Two nucleotide substitutions in each of the HPV-16 specific AUAGUA motifs alleviated splicing inhibition and induced late L1 mRNA production from episomal forms of the HPV-16 genome in primary human keratinocytes. The AUAGUA motifs bind specifically not only to the heterogeneous nuclear RNP (hnRNP) D family of RNA-binding proteins including hnRNP D/AUF, hnRNP DL and hnRNP AB but also to hnRNP A2/B1. Knock-down of these proteins induced HPV-16 late L1 mRNA expression, and overexpression of hnRNP A2/B1, hnRNP AB, hnRNP DL and the two hnRNP D isoforms hnRNP D37 and hnRNP D40 further suppressed L1 mRNA expression. This inhibition may allow HPV-16 to hide from the immune system and establish long-term persistent infections with enhanced risk at progressing to cancer. There is an inverse correlation between expression of hnRNP D proteins and hnRNP A2/B1 and HPV-16 L1 production in the cervical epithelium, as well as in cervical cancer, supporting the conclusion that hnRNP D proteins and A2/B1 inhibit HPV-16 L1 mRNA production.
authors.affiliation: Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, 221 84 Lund, Sweden.
authors.forename: Xiaoze
authors.initials: X
authors.lastname: Li
authors.forename: Cecilia
authors.initials: C
authors.lastname: Johansson
authors.forename: Jacob
authors.initials: J
authors.lastname: Glahder
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Mossberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwartz
mesh_terms: D001665:Binding Sites; D036022:Capsid Proteins / Q000096:biosynthesis / Q000235:genetics*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D015603:Keratinocytes / Q000821:virology; D059372:Nucleotide Motifs; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics*; D022821:RNA Splice Sites; D012326:RNA Splicing; D012333:RNA, Messenger / Q000096:biosynthesis; D012367:RNA, Viral / Q000737:chemistry*; D038621:Regulatory Sequences, Ribonucleic Acid; D017384:Sequence Deletion
chemical_list: D036022:Capsid Proteins; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D009856:Oncogene Proteins, Viral; D022821:RNA Splice Sites; D012333:RNA, Messenger; D012367:RNA, Viral; D038621:Regulatory Sequences, Ribonucleic Acid; C063317:L1 protein, Human papillomavirus type 16