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

Journal article

Knight, Gillian L., Pugh, Alice G., Yates, Emma, Bell, Ian, Wilson, Regina, Moody, Cary A., Laimins, Laimonis A. and Roberts, Sally 2013. 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. Virology. https://doi.org/10.1016/j.virol.2011.01.007
AuthorsKnight, Gillian L., Pugh, Alice G., Yates, Emma, Bell, Ian, Wilson, Regina, Moody, Cary A., Laimins, Laimonis A. and Roberts, Sally
Abstract

Investigation into the effects the HPV E4 protein has in viral life cycle

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 (43RRLL46) 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.

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 (43RRLL46) 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.

KeywordsHPV; Cervical cancer
Year2013
JournalVirology
ISSN00426822
Digital Object Identifier (DOI)https://doi.org/10.1016/j.virol.2011.01.007
Web address (URL)http://hdl.handle.net/10545/274327
hdl:10545/274327
Publication dates20 Mar 2013
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Deposited20 Mar 2013, 15:02
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