GADD34 is a modulator of autophagy during starvation

Gennaro Gambardella, Leopoldo Staiano, Maria Nicoletta Moretti, Rossella De Cegli, Luca Fagnocchi, Giuseppe Di Tullio, Sara Polletti, Clarissa Braccia, Andrea Armirotti, Alessio Zippo, Andrea Ballabio, Maria Antonietta De Matteis, Diego Di Bernardo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbereabb0205
JournalScience advances
Volume6
Issue number39
DOIs
Publication statusPublished - Sep 2020

ASJC Scopus subject areas

  • General

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