The role of protein kinase A regulation of the E6 PDZ-binding domain during the differentiation-dependent life cycle of human papillomavirus type 18.

Journal article


Delury, Craig P, Marsh, Elizabeth K, James, Claire D, Boon, Siaw Shi, Banks, Lawrence, Knight, Gillian L and Roberts, Sally 2013. The role of protein kinase A regulation of the E6 PDZ-binding domain during the differentiation-dependent life cycle of human papillomavirus type 18. Journal of Virology. https://doi.org/10.1128/JVI.01234-13
AuthorsDelury, Craig P, Marsh, Elizabeth K, James, Claire D, Boon, Siaw Shi, Banks, Lawrence, Knight, Gillian L and Roberts, Sally
Abstract

Human papillomavirus (HPV) E6 proteins of high-risk alpha types target a select group of PSD95/DLG1/ZO1 (PDZ) domain-containing proteins by using a C-terminal PDZ-binding motif (PBM), an interaction that can be negatively regulated by phosphorylation of the E6 PBM by protein kinase A (PKA). Here, we have mutated the canonical PKA recognition motif that partially overlaps with the E6 PBM in the HPV18 genome (E6153PKA) and compared the effect of this mutation on the HPVl8 life cycle in primary keratinocytes with the wild-type genome and with a second mutant genome that lacks the E6 PBM (E6ΔPDZ). Loss of PKA recognition of E6 was associated with increased growth of the genome-containing cells relative to cells carrying the wild-type genome, and upon stratification, a more hyperplastic phenotype, with an increase in the number of S-phase competent cells in the upper suprabasal layers, while the opposite was seen with the E6ΔPDZ genome. Moreover, the growth of wild-type genome-containing cells was sensitive to changes in PKA activity, and these changes were associated with increased phosphorylation of the E6 PBM. In marked contrast to E6ΔPDZ genomes, the E6153PKA mutation exhibited no deleterious effects on viral genome amplification or expression of late proteins. Our data suggest that the E6 PBM function is differentially regulated by phosphorylation in the HPV18 life cycle. We speculate that perturbation of protein kinase signaling pathways could lead to changes in E6 PBM function, which in turn could have a bearing on tumor promotion and progression.

KeywordsHuman papillomavirus (HPV); PDZ proteins
Year2013
JournalJournal of Virology
PublisherAmerican Society for Microbiology
ISSN1098-5514
Digital Object Identifier (DOI)https://doi.org/10.1128/JVI.01234-13
Web address (URL)http://hdl.handle.net/10545/623841
http://creativecommons.org/licenses/by-nc-nd/3.0/us/
hdl:10545/623841
Publication dates13 Aug 2013
Publication process dates
Deposited12 Jun 2019, 10:36
Accepted20 Jun 2013
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Attribution-NonCommercial-NoDerivs 3.0 United States

ContributorsUniversity of Birmingham
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