Universität zu Köln

Marx, Benjamin, Miller-Lazic, Daliborka, Doorbar, John, Majewski, Slawomir, Hofmann, Kay ORCID: 0000-0002-2289-9083, Hufbauer, Martin and Akguel, Baki (2017). HPV8-E6 Interferes with Syntenin-2 Expression through Deregulation of Differentiation, Methylation and Phosphatidylinositide-Kinase Dependent Mechanisms. Front. Microbiol., 8. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-302X

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Abstract

The E6 oncoproteins of high-risk human papillomaviruses (HPV) of genus alpha contain a short peptide sequence at the carboxy-terminus, the PDZ binding domain, with which they interact with the corresponding PDZ domain of cellular proteins. Interestingly, E6 proteins from papillomaviruses of genus beta (betaPV) do not encode a comparable PDZ binding domain. Irrespective of this fact, we previously showed that the E6 protein of HPV8 (betaPV type) could circumvent this deficit by targeting the PDZ protein Syntenin-2 through transcriptional repression (Lazic et al., 2012). Despite its high binding affinity to phosphatidylinositol-4,5-bisphosphate (PI(4,5) P-2), very little is known about Syntenin-2. This study aimed to extend the knowledge on Syntenin-2 and how its expression is controlled. We now identified that Syntenin-2 is expressed at high levels in differentiating and in lower amounts in keratinocytes cultured in serum-free media containing low calcium concentration. HPV8-E6 led to a further reduction of Syntenin-2 expression only in cells cultured in low calcium. In the skin of patients suffering from Epidermodysplasia verruciformis, who are predisposed to betaPV infection, Syntenin-2 was expressed in differentiating keratinocytes of non-lesional skin, but was absent in virus positive squamous tumors. Using 5-Aza-2'-deoxycytidine, which causes DNA demethylation, Syntenin-2 transcription was profoundly activated and fully restored in the absence and presence of HPV8-E6, implicating that E6 mediated repression of Syntenin-2 transcription is due to promoter hypermethylation. Since Syntenin-2 binds to PI(4,5)P-2, we further tested whether the PI(4,5)P-2 metabolic pathway might govern Syntenin-2 expression. PI(4,5)P-2 is generated by the activity of phosphatidylinositol-4-phosphate-5-kinase type I (PIP5KI) or phosphatidylinositol-5-phosphate-4-kinase type II (PIP4KII) isoforms alpha, beta and gamma. Phosphatidylinositide kinases have recently been identified as regulators of gene transcription. Surprisingly, transfection of siRNAs directed against PIP5KI and PIP4KII resulted in higher Syntenin-2 expression with the highest effect mediated by siPIP5KI alpha. HPV8-E6 was able to counteract siPIP4KII alpha, siPIP4KII beta and siPIP5KI gamma mediated Syntenin-2 re-expression but not siPIP5KI alpha. Finally, we identified Syntenin-2 as a key factor regulating PIP5KI alpha expression. Collectively, our data demonstrates that Syntenin-2 is regulated through multiple mechanisms and that downregulation of Syntenin-2 expression may contribute to E6 mediated dedifferentiation of infected skin cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Marx, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Miller-Lazic, Daliborka UNSPECIFIED UNSPECIFIED UNSPECIFIED Doorbar, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Majewski, Slawomir UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Kay UNSPECIFIED orcid.org/0000-0002-2289-9083 UNSPECIFIED Hufbauer, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Akguel, Baki UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-217903
DOI:	10.3389/fmicb.2017.01724
Journal or Publication Title:	Front. Microbiol.
Volume:	8
Date:	2017
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1664-302X
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN PAPILLOMAVIRUSES; E6 PROTEIN; MALIGNANT-TRANSFORMATION; PDZ PROTEIN; II-GAMMA; HPV; E7; KERATINOCYTES; LOCALIZATION; TRAFFICKING Multiple languages Microbiology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21790