Translation Inhibitors Activate Autophagy Master Regulators TFEB and TFE3

Abstract

The autophagy-lysosome pathway is a major protein degradation pathway stimulated by multiple cellular stresses, including nutrient or growth factor deprivation, hypoxia, misfolded proteins, damaged organelles, and intracellular pathogens. Recent studies have revealed that transcription factor EB (TFEB) and transcription factor E3 (TFE3) play a pivotal role in the biogenesis and functions of autophagosome and lysosome. Here we report that three translation inhibitors (cycloheximide, lactimidomycin, and rocaglamide A) can facilitate the nuclear translocation of TFEB/TFE3 via dephosphorylation and 14-3-3 dissociation. In addition, the inhibitor-mediated TFEB/TFE3 nuclear translocation significantly increases the transcriptional expression of their downstream genes involved in the biogenesis and function of autophagosome and lysosome. Furthermore, we demonstrated that translation inhibition increased autophagosome biogenesis but impaired the degradative autolysosome formation because of lysosomal dysfunction. These results highlight the previously unrecognized function of the translation inhibitors as activators of TFEB/TFE3, suggesting a novel biological role of translation inhibition in autophagy regulation.

Porcine Reproductive and Respiratory Syndrome Virus nsp5 Induces Incomplete Autophagy by Impairing the Interaction of STX17 and SNAP29

“…Because of the critical role of autophagy in protein degradation and the subsequent recycling of amino acids for the upkeep of protein synthesis, a growing number of studies have focused on the association between autophagy and translation. Dang et al found that translation inhibitor-mediated translation shutoff promoted autophagosome biogenesis but blocked the formation of degradative autolysosomes by destroying functional lysosomes ( 57 ). Similar phenomena have also been observed during bacterial infections.…”

Emerging roles of TFE3 in metabolic regulation

“…TFE3 regulates metabolism by directly regulating autophagy depending on the nutritional status of the cell Several studies have revealed that TFE3 is a key regulator of autophagy and that autophagy is closely associated with the metabolic regulation of cells [82,83]. Metabolism regulation via autophagy is primarily achieved through the mammalian target of the rapamycin 1(mTOR1) pathway [84].…”

“…Autophagy and mTOR signaling pathways regulate cell metabolism during cell starvation and adequate nutritional conditions, respectively. TFE3 primarily enhances cell metabolism [82,83,96]. In general, TFE3 activates autophagy only when the mTOR signaling pathway is inactivated [5].…”

Regulation of Autophagy by the Glycogen Synthase Kinase-3 (GSK-3) Signaling Pathway

“…Autophagy is a cellular degradation process that delivers intercellular cargo to the lysosomes [30]. Autophagy can be triggered by cellular stress including nutrient deprivation and hypoxia [31]. Furthermore, autophagy can degrade long-lived proteins and organelles and recycle them to support cell survival [32].…”