The ubiquitin ligase E6AP mediates nonproteolytic polyubiquitylation of beta-catenin independent of the E6 oncoprotein
Details
Publication Year 2016-10-07, Volume 97, Issue #12, Page 3313-3330
Journal Title
J Gen Virol
Publication Type
Journal Article
Abstract
Recently we showed that the ubiquitin ligase E6AP stabilizes beta-catenin and activates its transcriptional activity. These activities were enhanced by the human papillomavirus (HPV) E6 protein. In the present study we explored the function of E6AP that increases beta-catenin stabilization and transcriptional activation. Here we report that E6AP interacts with beta-catenin and mediates its nonproteolytic ubiquitylation, as evidenced in transiently transfected cell-based, and in vitro reconstitution ubiquitylation assays. Overexpression of E6AP increased beta-catenin polyubiquitylation and consistent with that, knockdown or knockout of E6AP expression reduced beta-catenin polyubiquitylation. The ubiquitylation of beta-catenin by E6AP was dependent on its E3 ubiquitin ligase activity, but it was proteasome-independent, and did not require HPV-E6, phosphorylation of beta-catenin by GSK3beta, or activity of the beta-catenin "destruction complex". We also show that transcriptional activation of beta-catenin by E6AP is coupled with beta-catenin protein stabilization but not its ubiquitylation. Different from beta-catenin ubiquitylation, beta-catenin protein stability and its transcriptional activity were absolutely dependent on the activity of the "destruction complex" and phosphorylation by GSK3beta. Collectively, our data uncover a dual role for E6AP in the regulation of beta-catenin ubiquitylation, stability and transcriptional activity, with HPV-E6 enhancing only part of E6AP activities.
Publisher
Microbiology Society
WEHI Research Division(s)
Systems Biology And Personalised Medicine
PubMed ID
27902311
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2017-05-26 03:11:43
Last Modified: 2017-05-26 03:36:54
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