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.
Highlights
Human papillomavirus (HPV) is the most common sexually transmitted virus in the human population
We concluded that sequences immediately upstream of Human papillomavirus type 16 (HPV-16) late 50splice site SD3632 inhibit production of spliced L1 mRNA
CAT units obtained in transfections with various HPV-16-CAT plasmids were divided by the CAT units produced by pCMVCAT16 and thereafter multiplied by 104 to generate the rCAT values displayed in each figure, as described in ‘Materials and Methods’ section
Summary
Human papillomavirus (HPV) is the most common sexually transmitted virus in the human population. HPV is present in 99.7% of all cervical cancers and is tightly associated with several other anogenital cancers and head and neck cancers [2]. Half of the human cancers, which are caused by viruses are attributable to HPVs, and cervical cancer is one of the main causes of death in women in the developing world [3]. A subset of the sexually transmitted HPV types has been associated with cancer and is termed high-risk HPV types. HPV type 16 is the most common high-risk type in HPV-induced cancers as well as in the human population [4,5]
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