GADD34 is a modulator of autophagy during starvation

Sci Adv. 2020 Sep 25;6(39):eabb0205. doi: 10.1126/sciadv.abb0205.

Gennaro Gambardella ¹ ², Leopoldo Staiano ¹, Maria Nicoletta Moretti ¹, Rossella De Cegli ¹, Luca Fagnocchi ³ ⁴, Giuseppe Di Tullio ¹, Sara Polletti ⁵, Clarissa Braccia ⁶, Andrea Armirotti ⁶, Alessio Zippo ³ ⁴, Andrea Ballabio ¹ ⁷ ⁸, Maria Antonietta De Matteis ⁹ ¹⁰, Diego di Bernardo ⁹ ²

Affiliations

1 Telethon Institute of Genetics and Medicine, Naples, Italy.
2 University of Naples Federico II, Department of Chemical Materials and Industrial Engineering, Naples, Italy.
3 Istituto Nazionale di Genetica Molecolare "Romeo ed Erica Invernizzi" (INGM), Milan, Italy.
4 Chromatin Biology & Epigenetics Lab, Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
5 Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy.
6 Italian Institute of Technology (IIT), Genoa, Italy.
7 University of Naples Federico II, Department of Medical and Translation Science, Naples, Italy.
8 Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.
9 Telethon Institute of Genetics and Medicine, Naples, Italy. dematteis@tigem.it dibernardo@tigem.it.
10 University of Naples Federico II, Department of Medical Biotechnologies and Molecular Medicine, Naples, Italy.

PMID: 32978159 DOI: 10.1126/sciadv.abb0205

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 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.

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