# Differential contribution of TFE3 isoforms to cell motility and invasion

## TL;DR

This study shows that two TFE3 protein versions, TFE3-L and TFE3-S, have similar roles in stress response but differ in how well they promote cell movement and invasion.

## Contribution

The discovery that TFE3-L is more effective than TFE3-S in promoting cell migration and invasion is novel.

## Key findings

- TFE3-L is degraded under normal conditions but accumulates during prolonged stress.
- TFE3-S is constantly present and mediates early stress responses.
- TFE3-L is more efficient than TFE3-S in promoting cell motility and invasion.

## Abstract

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.

Two distinct TFE3 isoforms, TFE3 long (TFE3-L) and TFE3 short (TFE3-S), generated by the use of alternative transcription initiation sites have shared and distinct functions.

TFE3-L undergoes proteasomal degradation in basal conditions due to the presence of a phosphodegron and only accumulates following prolonged stress.TFE3-S lacks the phosphodegron and is constitutively expressed, thus mediating early stress responses.The two isoforms show partial redundancy, while both induce comparable upregulation of lysosomal and autophagy genes, TFE3-L is more efficient promoting cell motility and invasion.

TFE3-L undergoes proteasomal degradation in basal conditions due to the presence of a phosphodegron and only accumulates following prolonged stress.

TFE3-S lacks the phosphodegron and is constitutively expressed, thus mediating early stress responses.

The two isoforms show partial redundancy, while both induce comparable upregulation of lysosomal and autophagy genes, TFE3-L is more efficient promoting cell motility and invasion.

Two distinct TFE3 isoforms, TFE3 long (TFE3-L) and TFE3 short (TFE3-S), generated by the use of alternative transcription initiation sites have shared and distinct functions.