Journal
SCIENCE ADVANCES
Volume 6, Issue 39, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abb0205
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Funding
- Fondazione Telethon [TMDDSB116TT, TGM11CB1]
- Italian Association for Cancer Research (AIRC) [IG2013_14761]
- European Research Council [694282]
- Junior PI STAR grant from the University of Naples Federico II
- European Research Council H2020 AdG LYSOSOMICS [694282]
- European Research Council (ERC) [694282] Funding Source: European Research Council (ERC)
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Cells respond to starvation by shutting down protein synthesis and by activating catabolic processes, including autophagy, to recycle nutrients. This two-pronged response is mediated by the integrated stress response (ISR) through phosphorylation of eIF2 alpha, which represses protein translation, and by inhibition of mTORC1 signaling, which promotes autophagy also through a stress-responsive transcriptional program. Implementation of such a program, however, requires protein synthesis, thus conflicting with general repression of translation. How is this mismatch resolved? We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2 alpha. We discovered that GADD34 plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux. Hence, the TFEB-GADD34 axis integrates the mTORC1 and ISR pathways in response to starvation.
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