TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration

PLoS Biol. 2013 Dec;11(12):e1001726. doi: 10.1371/journal.pbio.1001726. Epub 2013 Dec 3.

Abstract

Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is frequently overexpressed in carcinomas, suggesting a specific role in cancer. Although TRAF4 protein is predominantly found at tight junctions (TJs) in normal mammary epithelial cells (MECs), it accumulates in the cytoplasm of malignant MECs. How TRAF4 is recruited and functions at TJs is unclear. Here we show that TRAF4 possesses a novel phosphoinositide (PIP)-binding domain crucial for its recruitment to TJs. Of interest, this property is shared by the other members of the TRAF protein family. Indeed, the TRAF domain of all TRAF proteins (TRAF1 to TRAF6) is a bona fide PIP-binding domain. Molecular and structural analyses revealed that the TRAF domain of TRAF4 exists as a trimer that binds up to three lipids using basic residues exposed at its surface. Cellular studies indicated that TRAF4 acts as a negative regulator of TJ and increases cell migration. These functions are dependent from its ability to interact with PIPs. Our results suggest that TRAF4 overexpression might contribute to breast cancer progression by destabilizing TJs and favoring cell migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Membrane / physiology
  • Cell Movement / physiology*
  • Chlorocebus aethiops
  • Humans
  • Phosphatidylinositols / physiology
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 4 / physiology*
  • Tight Junctions / physiology*

Substances

  • Phosphatidylinositols
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 4
  • TRAF4 protein, human

Grant support

This work was supported by a grant from the Ligue Contre le Cancer (Conférence de Coordination Interrégionale du Grand Est; http://www.ligue-cancer.net/cd71/actions-missions/la-recherche). We acknowledge funds from the Institut National de Santé et de Recherche Médicale (http://www.inserm.fr/), the Centre National de la Recherche Scientifique (http://www.cnrs.fr/), and the Université de Strasbourg (http://www.uds.fr/). This work was also supported by the French Infrastructure for Integrated Structural Biology (FRISBI; https://www.structuralbiology.eu/networks/frisbi) ANR-10-INSB-05-01, and Instruct as part of the European Strategy Forum on Research Infrastructures (ESFRI), as well as the Fondation ARC (http://www.arc-cancer.net/; contract 8008). AR received an allocation from the Ministère de l'Enseignement Supérieur et de la Recherche (France; http://www.enseignementsup-recherche.gouv.fr/) and a fellowship from the Ligue Nationale Contre le Cancer (http://www.ligue-cancer.net/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.