Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/ijms222112083
Keywords
autophagy-lysosome pathway; TFEB; TFEB nuclear translocation; mTOR; calcineurin; ribosome; eIF4A helicase; translation inhibitor
Funding
- Basic Science Research Program [2017R1D1A1B03028229, 2020R1F1A1066088]
- Bio and Medical Technology Development Program [2017M3A9G7072745]
- Priority Research Centers Program [2014R1A6A1030318]
- National Research Foundation of Korea
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Recent studies have shown that translation inhibitors can facilitate the nuclear translocation of transcription factors EB (TFEB) and E3 (TFE3), leading to increased expression of downstream genes involved in autophagosome and lysosome biogenesis and function. However, translation inhibition also impairs degradative autolysosome formation due to lysosomal dysfunction. This highlights a novel biological role of translation inhibition in autophagy regulation.
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.
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