Recombinant Human papillomavirus type 16 protein E4 (E4)

Function

Contributes to multiple aspects of the viral life cycle including viral genome amplification, suppression of suprabasal cell differentiation and egress of newly formed virions. Induces host cell cycle arrest at the G2 phase by associating with and preventing the nuclear entry of host CDK1/cyclin B1 complexes. Inhibits cellular DNA replication by preventing loading of host replication licensing proteins MCM2 and MCM7 onto chromatin. Within the cytoplasm, associates with host kinase SRPK1, a splicing factor regulator, and inhibits its activity. Therefore, E4 favors expression of late viral transcripts by inhibiting SRPK1-mediated phosphorylation of host serine-arginine (SR) proteins that have critical roles in mRNA metabolism. Late in the infectious cycle, E4 also acts to diminish the integrity of the keratinocyte by disrupting the keratin cytoskeleton and inducing apoptosis through alteration of mitochondrial function to facilitate egress of the newly formed virions

Subcellular Location

Host cytoplasm; Host nucleus

Subunit

Assembles into oligomeric complexes. Interacts with host CDK1. Interacts with host SRPK1; this interaction may favor expression of late viral transcripts. Interacts with host cytokeratin components KRT8 and KRT18

• Seedorf K. et al. Human papillomavirus type 16 DNA sequence. — Virology (1985)
• Terai M. et al. Cloning and sequencing of non-European human papillomavirus (HPV) variant complete genomes from cervicovaginal cells by an overlapping PCR method. (AUG-)
• Schneider-Maunoury S. et al. Expression of the human papillomavirus type 16 genome in SK-v cells, a line derived from a vulvar intraepithelial neoplasia. — J. Gen. Virol. (1990)
• Roberts S. et al. Mutational analysis of human papillomavirus E4 proteins: identification of structural features important in the formation of cytoplasmic E4/cytokeratin networks in epithelial cells. — J. Virol. (1994)
• Davy C.E. et al. Identification of a G(2) arrest domain in the E1 wedge E4 protein of human papillomavirus type 16. — J. Virol. (2002)
• Wang Q. et al. Functional analysis of the human papillomavirus type 16 E1=E4 protein provides a mechanism for in vivo and in vitro keratin filament reorganization. — J. Virol. (2004)
• Davy C.E. et al. Human papillomavirus type 16 E1 E4-induced G2 arrest is associated with cytoplasmic retention of active Cdk1/cyclin B1 complexes. — J. Virol. (2005)
• Davy C.E. et al. HPV16 E1--E4 protein is phosphorylated by Cdk2/cyclin A and relocalizes this complex to the cytoplasm. — Virology (2006)