PT  - JOURNAL ARTICLE
AU  - Gambardella, Gennaro
AU  - Staiano, Leopoldo
AU  - Moretti, Maria Nicoletta
AU  - De Cegli, Rossella
AU  - Fagnocchi, Luca
AU  - Di Tullio, Giuseppe
AU  - Polletti, Sara
AU  - Braccia, Clarissa
AU  - Armirotti, Andrea
AU  - Zippo, Alessio
AU  - Ballabio, Andrea
AU  - De Matteis, Maria Antonietta
AU  - di Bernardo, Diego
TI  - GADD34 is a modulator of autophagy during starvation
AID  - 10.1126/sciadv.abb0205
DP  - 2020 Sep 01
TA  - Science Advances
PG  - eabb0205
VI  - 6
IP  - 39
4099  - http://advances.sciencemag.org/content/6/39/eabb0205.short
4100  - http://advances.sciencemag.org/content/6/39/eabb0205.full
SO  - Sci Adv2020 Sep 01; 6
AB  - 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 eIF2α, 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 eIF2α. 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.