A cyclin-binding motif in human papillomavirus type 18 (HPV18) E1^E4 is necessary for association with CDK–cyclin complexes and G2/M cell cycle arrest of keratinocytes, but is not required for differentiation-dependent viral genome amplification or L1 capsid protein expression

Abstract The G2/M arrest function of human papillomavirus (HPV) E4 proteins is hypothesized to be necessary for viral genome amplification. Full-length HPV18 E1^E4 protein is essential for efficient viral genome amplification. Here we identify key determinants within a CDK-bipartite consensus recogn...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2011-03, Vol.412 (1), p.196-210
Main Authors: Knight, Gillian L, Pugh, Alice G, Yates, Emma, Bell, Ian, Wilson, Regina, Moody, Cary A, Laimins, Laimonis A, Roberts, Sally
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Binding Sites
Capsid Proteins - biosynthesis
CDK
Cell Cycle
Cells, Cultured
Cyclin B1
Cyclin-Dependent Kinases - metabolism
Cyclins - metabolism
E1^E4
G2 arrest
G2/M arrest
H genome amplification
HPV
HPV life cycle
Human papillomavirus
Human papillomavirus 18 - genetics
Human papillomavirus 18 - pathogenicity
Humans
Infectious Disease
Keratinocytes - physiology
Keratinocytes - virology
Oncogene Proteins, Fusion - metabolism
Protein Binding
Virulence Factors - metabolism
Virus Replication
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Summary:Abstract The G2/M arrest function of human papillomavirus (HPV) E4 proteins is hypothesized to be necessary for viral genome amplification. Full-length HPV18 E1^E4 protein is essential for efficient viral genome amplification. Here we identify key determinants within a CDK-bipartite consensus recognition motif in HPV18 E1^E4 that are critical for association with active CDK–cyclin complexes and in vitro phosphorylation at the predicted CDK phosphorylation site (threonine 23). The optimal cyclin-binding sequence (43 RRLL46 ) within this E4 motif is required for G2/M arrest of primary keratinocytes and correlates with cytoplasmic retention of cyclin B1, but not cyclin A. Disruption of this motif in the E4 ORF of HPV18 genomes, and the subsequent generation of stable cell lines in primary keratinocytes revealed that this motif was not essential for viral genome amplification or L1 capsid protein induction. We conclude that the HPV18 E4 G2/M arrest function does not play a role in early vegetative events.
ISSN:0042-6822
1096-0341
1096-0341
DOI:10.1016/j.virol.2011.01.007