Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Abstract

The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelium. This means that viral proteins must exert control over epithelial gene expression in order to optimize viral production. The HPV E2 protein controls replication, transcription, and viral genome partitioning during the viral infectious life cycle. It consists of a nucleic acid-binding domain and a protein-protein interaction domain separated by a flexible serine and arginine-rich hinge region. Over the last few years, mounting evidence has uncovered an important new role for E2 in viral and cellular RNA processing. This Gem discusses the role of E2 in controlling the epithelial cellular environment and how E2 might act to coordinate late events in the viral replication cycle. HUMAN PAPILLOMAVIRUS LIFE CYCLEH uman papillomaviruses (HPVs) are small (ϳ8.0-kbp) circular double-stranded DNA viruses that infect epithelial cells (keratinocytes) (1). There are more than 200 HPV genotypes. For the most part, HPVs of the ␣-genotype group infect mucosal epithelia, while the ␤-genotypes infect predominantly cutaneous epithelia (2). Most HPV infections are asymptomatic, or they manifest as benign lesions or warts. They are usually transient and are eventually cleared by the immune system (3). Despite this, HPVs cause a high burden of clinically significant disease worldwide, because the anogenital mucosa-infective high-risk group of HPVs (HR-HPVs) can cause persistent infection that leads to epithelial dysplasia and neoplasia. HR-HPVs are commonly associated with cervical cancer and tumors of other anogenital sites (2). Per annum, worldwide, there are around 500,000 new cases of cervical disease, and around 270,000 women die from cervical cancer. The two most prevalent HR-HPVs are HPV16 and -18, which are targeted by the current HPV vaccines (4). Over the last few decades, epidemic HR-HPV infection, especially in men, has been associated with a significant increase in oropharyngeal cancers (5). Certain cutaneous HPVs can also cause tumors (squamous cell carcinomas) in immunocompromised or immunosuppressed individuals (6). Thus, the causative association of HPV infection with a number of significant cancers indicates that increased understanding of the viral life cycle is essential.The HPV life cycle is intimately linked to epithelial differentiation (Fig. 1A) (2). HPV normally infects dividing cells at the base of the epithelium (basal layer) but completes its life cycle by amplifying progeny DNA genomes in the midepithelial layers (spinous layer) and carrying out viral encapsidation in the uppermost epithelial layer (granular layer) (Fig. 1A). Viral production is achieved through a highly orchestrated and complex viral gene expression program (Fig. 1A) (2). Mature virions are released upon shedding and disintegration of dead superficial epithelial cells into the environment. As a necessity, HPV infection alters the normal differentiation pattern of the epithelium and controls cellular gene expression to support viral re...

hnRNP L controls HPV16 RNA polyadenylation and splicing in an Akt kinase-dependent manner

“…In addition to cellular RNA binding proteins, HPV16 E2 contributes directly to the control of HPV16 RNA processing by interfering with HPV16 RNA polyadenylation ( 14 ). HPV16 E2 has also been shown to affect HPV16 RNA processing indirectly by activating expression of splicing factors ( 15 ), possibly a result of E2 binding to cellular DNA ( 16 ). Cellular factors such as CTCF may also control both transcription and processing of HPV mRNAs ( 17 ).…”

“…Cellular factors such as CTCF may also control both transcription and processing of HPV mRNAs ( 17 ). Much of HPV16 gene regulation occurs at the level of RNA processing ( 8 , 15 , 18 ) and HPVs produce a large number of alternatively spliced and polyadenylated mRNAs ( 9 ). A number of cis acting RNA elements controlling HPV16 and HPV18 splices sites and polyA signals have been identified and characterized ( 8 ), and a review of all identified HPV RNA binding proteins has recently been published ( 19 ).…”

Mitochondrial Proteins Coded by Human Tumor Viruses

“…E2 is a protein of about 365 amino acids (HPV genotype 16; its length varies among genotypes) whose expression gradually increases from the mid- to upper layers of infected lesions. This pattern of expression reflects the key role of E2 in the coordination of late events of viral replication through its influence on transcription, viral genome replication and partitioning in dividing cells, and RNA processing (reviewed by Graham, 2016 ).…”

Analysis of human papilloma virus type 52 integration status in exfoliated cervical cells

“…The present study has focused on this type of HPV. The HPV E2 protein controls replication, transcription and viral genome partitioning during the viral infectious life cycle ( 16 ). The HPV E2 protein is a key transcriptional regulator of the E6 and E7 genes ( 17 ).…”