To reestablish homeostasis and mitigate stress, cells must activate a series of adaptive intracellular signaling pathways. The participation of the transcription factors TFEB and TFE3 in cellular adaptation to starvation is well established. Here, we show that TFEB and TFE3 also play an important role in the cellular response to ER stress. Treatment with ER stressors causes translocation of TFEB and TFE3 to the nucleus in a process that is dependent on PERK and calcineurin but not on mTORC1. Activated TFEB and TFE3 enhance cellular response to stress by inducing direct transcriptional upregulation of ATF4 and other UPR genes. Under conditions of prolonged ER stress, TFEB and TFE3 contribute to cell death, thus revealing an unexpected role for these proteins in controlling cell fate. This work evidences a broader role of TFEB and TFE3 in the cellular response to stress than previously anticipated and reveals an integrated cooperation between different cellular stress pathways.
The transcription factors TFEB and TFE3 are activated upon starvation‐induced mTORC1 inhibition, but also respond to ER stress in a PERK‐dependent manner. This finding reveals a hitherto unknown level of crosstalk between cellular stress pathways.
ER stress activates TFEB and TFE3 through a process that requires PERK but not mTORC1.
TFEB and TFE3 modulate the Integrative Stress Response by regulating ATF4 expression both under ER stress and starvation conditions.
In response to stress TFE3 regulates not only autophagic and lysosomal genes, but also genes implicated in cellular homeostasis, stress response, signaling, and regulation of apoptosis.
TFEB and TFE3 play a dual role in cell fate by promoting either survival or cell death depending on the duration and strength of the stress.
The EMBO Journal (2016) 35: 479–495
- Received November 3, 2015.
- Revision received December 7, 2015.
- Accepted December 10, 2015.
- Published 2016. This article is a U.S. Government work and is in the public domain in the USA
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