Control of human papillomavirus gene expression by alternative splicing

• Published in: Virus research 2017-03, Vol.231, p.83-95
• Main Authors: Graham, Sheila V., Faizo, Arwa Ali A.
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Cell Differentiation; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; epithelial cells; epithelium; gene expression; Gene Expression Regulation, Viral; genome; Heterogeneous-Nuclear Ribonucleoproteins - genetics; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; hnRNP; Host-Pathogen Interactions; Human papillomavirus; Humans; Keratinocytes - metabolism; Keratinocytes - virology; Life cycle; messenger RNA; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - metabolism; Papillomaviridae; Papillomaviridae - genetics; Papillomaviridae - growth & development; Papillomaviridae - pathogenicity; Papillomavirus Infections - genetics; Papillomavirus Infections - metabolism; Papillomavirus Infections - pathology; Papillomavirus Infections - virology; proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Viral - genetics; RNA, Viral - metabolism; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Signal Transduction; SR protein; transcription (genetics); Transcription, Genetic; Virus Replication; viruses
• ISSN: 0168-1702; 1872-7492
• DOI: 10.1016/j.virusres.2016.11.016

•Alternative splicing is a key cellular mechanism controlling HPV gene expression.•Many cellular SR proteins and hnRNPs have been identified that bind and control production of viral mRNAs.•HPV16 E2 protein controls expression of SR proteins and has splicing-related functions.•HPV16 infection through its regulatory effects on splicing factors may significantly alter cellular gene expression and cellular metabolism. Human papillomaviruses possess circular double stranded DNA genomes of around 8kb in size from which multiple mRNAs are synthesized during an infectious life cycle. Although at least three viral promoters are used to initiate transcription, viral mRNAs are largely the product of processing of pre-mRNAs by alternative splicing and polyadenylation. The HPV life cycle and viral gene expression are tightly linked to differentiation of the epithelium the virus infects: there is an orchestrated production of viral mRNAs and proteins. In this review we describe viral mRNA expression and the roles of the SR and hnRNP proteins that respectively positively and negatively regulate splicing. We discuss HPV regulation of splicing factors and detail the evidence that the papillomavirus E2 protein has splicing-related activities. We highlight the possibility that HPV-mediated control of splicing in differentiating epithelial cells may be necessary to accomplish the viral replication cycle.