USP9x-mediated deubiquitination of EFA6 regulates de novo tight junction assembly

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Title USP9x-mediated deubiquitination of EFA6 regulates de novo tight junction assembly
Author Theard, Delphine; Labarrade, Florian; Partisani, Mariagrazia; Milanini, Julie; Sakagami, Hiroyuki; Fon, Edward A; Wood, Stephen Andrew; Franco, Michel; Luton, Frederic
Journal Name The EMBO Journal
Year Published 2010
Place of publication United Kingdom
Publisher Nature Publishing Group
Abstract In epithelial cells, the tight junction (TJ) functions as a permeability barrier and is involved in cellular differentiation and proliferation. Although many TJ proteins have been characterized, little is known about the sequence of events and temporal regulation of TJ assembly in response to adhesion cues. We report here that the deubiquitinating enzyme USP9x has a critical function in TJ biogenesis by controlling the levels of the exchange factor for Arf6 (EFA6), a protein shown to facilitate TJ formation, during a narrow temporal window preceding the establishment of cell polarity. At steady state, EFA6 is constitutively ubiquitinated and turned over by the proteasome. However, at newly forming contacts, USP9x-mediated deubiquitination protects EFA6 from proteasomal degradation, leading to a transient increase in EFA6 levels. Consistent with this model, USP9x and EFA6 transiently co-localize at primordial epithelial junctions. Furthermore, knockdown of either EFA6 or USP9x impairs TJ biogenesis and EFA6 overexpression rescues TJ biogenesis in USP9x-knockdown cells. As the loss of cell polarity is a critical event in the metastatic spread of cancer, these findings may help to understand the pathology of human carcinomas.
Peer Reviewed Yes
Published Yes
Alternative URI
Volume 29
Issue Number 9
Page from 1499
Page to 1509
ISSN 0261-4189
Date Accessioned 2010-11-05
Language en_AU
Research Centre Eskitis Institute for Drug Discovery
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Animal Cell and Molecular Biology
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1

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