Differential contribution of TFE3 isoforms to cell motility and invasion

TFE3 orchestrates cellular responses to a variety of stress conditions, promoting restoration of cellular homeostasis and cell survival. Here we report the presence of two different TFE3 isoforms generated by the use of alternative transcription initiation sites. The long isoform (TFE3-L) undergoes continuous proteolytic degradation due to the presence of a phosphodegron in its N-terminal region and only accumulates under specific stress conditions. In contrast, the short isoform (TFE3-S) lacks the first 105 residues containing the phosphodegron and is constitutively expressed at high levels in most cell types. Both isoforms share the same Rags/mTORC1-dependent mechanism of regulation and display comparable capacity of inducing expression of lysosomal and autophagic genes upon activation. However, TFE3-L is considerably more efficient than TFE3-S promoting cell migration and invasion. Accordingly, specific TFE3-L depletion in a cellular model for tuberous sclerosis causes a significant reduction in cell motility and invasiveness. Our data reveal that the two TFE3 isoforms exhibit partial redundancy and that the appearance of TFE3-L following prolonged stress potentially correlates with metastatic behaviors.