Abstract
Author SummaryTumor necrosis factor (TNF) receptor-associated factor 4, also known as TRAF4, is an unusual member of the TRAF protein family. While TRAFs are primarily known as regulators of inflammation, antiviral responses, and apoptosis, research on TRAF4 has identified its involvement in development and cancer. Importantly TRAF4 overexpression has been associated with a poor prognosis in breast cancers. TRAF4 has multiple subcellular localizations: to the plasma membrane in tight junctions (TJs), cytoplasmic and nuclear. The recruitment mechanisms and the functional impact of these distinct localizations are not completely understood. Here we investigate how TRAF4 is recruited to TJs and its involvement in cell–cell contacts in mammary epithelial cells (MECs). We show that the TRAF domain of all TRAFs contains a lipid binding module, and that TRAF4 uses this domain to form a trimeric complex that associates with phosphoinositides at the plasma membrane. Moreover this interaction is necessary for its recruitment to TJs. Additionally, we show that through its interaction with lipids TRAF4 delays TJ assembly and increases cell migration. We propose that TRAF4 has an important function in cancer progression by destabilizing TJs and favoring cell migration.
Highlights
Tumor necrosis factor receptor-associated factor 4 (TRAF4) was originally identified as a gene overexpressed in breast carcinoma [1,2]
In cells stably expressing a shRNA specific for TRAF4 (MCF10A/shT4), TRAF4 expression was reduced to less than 10% compared to parental MCF10A cells and to cells expressing a control shRNA (MCF10A/shCtrl)
Our results indicate that TRAF4 is a negative regulator of tight junction (TJ) in mammary epithelial cell (MEC) (Figure 1), and the tumor necrosis factor receptor-associated factor (TRAF) domain is a novel PIP-binding domain that is essential for the addressing of the protein to the plasma membrane
Summary
Tumor necrosis factor receptor-associated factor 4 (TRAF4) was originally identified as a gene overexpressed in breast carcinoma [1,2]. TRAF4 belongs to the TRAF family that is composed of seven members in humans [5,6]. Among the seven TRAF family members, TRAF4 is one of the most conserved during evolution [7]. One of the three fly TRAF proteins, dTRAF1, shares the highest homology with human TRAF4 [9,10]. Surviving adult TRAF4-deficient mice exhibited ataxia, associated with myelination alteration [15]. Together, these various genetic models suggest that TRAF4 has an essential function conserved in most, if not all, pluricellular animals
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