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?, 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?. 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.

GADD34 is a modulator of autophagy during starvation / Gambardella, G.; Staiano, L.; Moretti, M. N.; De Cegli, R.; Fagnocchi, L.; Di Tullio, G.; Polletti, S.; Braccia, C.; Armirotti, A.; Zippo, A.; Ballabio, A.; De Matteis, M. A.; Di Bernardo, D.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 6:39(2020), pp. eabb020511-eabb020511. [10.1126/sciadv.abb0205]

GADD34 is a modulator of autophagy during starvation

Gambardella G.;Fagnocchi L.;Zippo A.;
2020

Abstract

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?, 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?. 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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Gambardella, G.; Staiano, L.; Moretti, M. N.; De Cegli, R.; Fagnocchi, L.; Di Tullio, G.; Polletti, S.; Braccia, C.; Armirotti, A.; Zippo, A.; Ballabio, A.; De Matteis, M. A.; Di Bernardo, D.
GADD34 is a modulator of autophagy during starvation / Gambardella, G.; Staiano, L.; Moretti, M. N.; De Cegli, R.; Fagnocchi, L.; Di Tullio, G.; Polletti, S.; Braccia, C.; Armirotti, A.; Zippo, A.; Ballabio, A.; De Matteis, M. A.; Di Bernardo, D.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 6:39(2020), pp. eabb020511-eabb020511. [10.1126/sciadv.abb0205]
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