RT Journal Article
SR Electronic
T1 GADD34 is a modulator of autophagy during starvation
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eabb0205
DO 10.1126/sciadv.abb0205
VO 6
IS 39
A1 Gambardella, Gennaro
A1 Staiano, Leopoldo
A1 Moretti, Maria Nicoletta
A1 De Cegli, Rossella
A1 Fagnocchi, Luca
A1 Di Tullio, Giuseppe
A1 Polletti, Sara
A1 Braccia, Clarissa
A1 Armirotti, Andrea
A1 Zippo, Alessio
A1 Ballabio, Andrea
A1 De Matteis, Maria Antonietta
A1 di Bernardo, Diego
YR 2020
UL http://advances.sciencemag.org/content/6/39/eabb0205.abstract
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.