Abstract
Expression of cofilin is directly associated with metastatic activity in many tumors. Here, we studied the role of Latent Membrane Protein 2 A (LMP2A) of Epstein-Barr Virus (EBV) in the accumulation of cofilin observed in nasopharyngeal cancer (NPC) tumor cells. We used LMP2A transformed NPC cell lines to analyze cofilin expression. We used mutation analysis, ectopic expression and down-regulation of Cbl, AIP4 and Syk in these cell lines to determine the effect of the LMP2A viral protein on cofilin degradation and its role in the assembly of a cofilin degrading protein complex. The LMP2A of EBV was found to interfer with cofilin degradation in NPC cells by accelerating the proteasomal degradation of Cbl and Syk. In line with this, we found significantly higher cofilin expression in NPC tumor samples as compared to the surrounding epithelial tissues. Cofilin, as an actin severing protein, influences cellular plasticity, and facilitates cellular movement in response to oncogenic stimuli. Thus, under relaxed cellular control, cofilin facilitates tumor cell movement and dissemination. Interference with its degradation may enhance the metastatic potential of NPC cells.
Highlights
Close to 100% of non-keratinizing nasopharyngeal carcinomas (NPC) are associated with EBV1
In lanes 3 and 4 we show that cofilin is detected in Latent Membrane Protein 2 A (LMP2A) immunoprecipitates from LMP2A expressing cells but not from LMP2A negative cells and is not detected in immunoprecipitates with an irrelevant antibody
We show that cofilin is up-regulated in LMP2A positive cells already at the gene expression level (Fig. S1)
Summary
Close to 100% of non-keratinizing nasopharyngeal carcinomas (NPC) are associated with EBV1. Latent Membrane protein 2 A (LMP2A) is commonly detected in EBV-positive NPC cells in vivo[4]. LMP2A associates with Syk at an ITAM tyrosine motif and with the E3 ubiquitin ligase AIP4 at a tandem WW domain, both of which are located within the N-terminal 119 amino acid long intracellular domain[9]. Cbl ubiquitin ligases function as negative regulators of cell signaling[11]. We provide evidence that a direct interaction with proteins in the LMP2A-assembled signalling scaffold interferes with the proteasomal degradation of cofilin. Our analysis of cofilin ubiquitination further suggests that cofilin is subject to ubiquitination by two E3 ubiquitin ligases, Cbl and AIP4, both components of the LMP2A signaling scaffold with different effects on cofilin stability and function. We test the impact of LMP2A on cofilin and cellular migration through perturbations of the proteasomal system
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