Regulation of splicing-associated SR proteins by HPV-16

Abstract

HPV-16 (human papillomavirus type 16) is a small dsDNA (double-stranded DNA) virus which infects mucosal epithelial tissue of the cervix. Epithelial tissue is composed of a basal layer of cells, capable of division, and a number of suprabasal layers, wherein the cells become more differentiated the closer to the surface of the epithelium they become. Expression of viral proteins is dependent upon epithelial differentiation status, and, within the HPV-16 genome, several elements have been found which control expression both transcriptionally and post-transcriptionally. Expression of the highly immunogenic capsid proteins, L1 and L2, is restricted to only the most differentiated cells, where immune surveillance is limited. However, L1 and L2 transcripts can be detected in less differentiated cells, suggesting post-transcriptional mechanisms exist to prevent their expression in these cells. Indeed, a number of cis-acting RNA elements have been observed within the HPV-16 late region which may be involved in control of capsid gene expression. Mechanisms controlling HPV-16 capsid gene expression and the cellular RNA-processing factors involved will be the focus of this article.

Development and validation of a novel reporter assay for human papillomavirus type 16 late gene expression

“…In fact, inactivation of the E4 enhancer and the L1 splicing silencers in a subgenomic HPV-16 plasmid showed production only of L1 mRNA (L1i), but not E4 mRNA Schwartz et al, 2007). Cellular RNA binding factors and viral RNA elements have shown to have a pivotal role in HPV-16 gene regulation Mole et al, 2006;Schwartz et al, 2007).…”

Virology and molecular pathogenesis of HPV (human papillomavirus)associated oropharyngeal squamous cell carcinoma

“…Some of these genes were subsequently validated to independently and additively mediate E2 induced repression, including the cellular demethylase JARID1C/SMCX and EP400, a component of the NuA4/TIP60 histone acetyltransferase complex. High-risk HPV E2 has also been demonstrated to transactivate and upregulate SR (serine/arginine-rich) proteins, highly conserved host splicing regulators for alternative splicing that are co-opted to participate in viral RNA processing and can act as oncoproteins [89, 90]. This leads to dysregulation of the tightly controlled process of constitutive and alternative splicing of host genes and elaborates the involvement of E2 in the pathogenesis of HPV induced malignancies.…”

Adenovirus E4orf4 induces HPV-16 late L1 mRNA production

“…Papillomaviruses produce a large number of alternatively spliced mRNAs (Baker and Calef,1997). At the RNA level, regulatory RNA elements, and the factors they interact with, must be present on the viral genome to prevent usage of late splice sites or polyadenylation signals at an early stage of the viral replication cycle (Mole et al, 2006;Schwartz, 2008;Schwartz et al, 2007;Zheng and Baker, 2006). On the other hand, other regulatory RNA elements are probably needed to induce late gene expression at the appropriate time during a productive HPV-16 infection (Mole et al, 2006;Schwartz, 2008;Schwartz et al, 2007;Zheng and Baker, 2006).…”