The ubiquitin ligase E6AP mediates nonproteolytic polyubiquitylation of beta-catenin independent of the E6 oncoprotein

Kuslansky, Y; Sominsky, S; Jackman, A; Gamell, C; Monahan, BJ; Haupt, Y; Rosin-Arbesfeld, R; Sherman, L

Author(s): Kuslansky, Y; Sominsky, S; Jackman, A; Gamell, C; Monahan, BJ; Haupt, Y; Rosin-Arbesfeld, R; Sherman, L;
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
Research Division(s): Systems Biology And Personalised Medicine
PubMed ID: 27902311
Publisher's Version: https://doi.org/10.1099/jgv.0.000624
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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Last Modified: 2017-05-26 03:36:54