Proteomics

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TFEB regulates protein synthesis to sustain autophagy during starvation

ABSTRACT: In response to starvation, cells undergo a metabolic shift to ensure their survival by shutting down protein synthesis and activating catabolic processes, including autophagy, to degrade proteins and recycle nutrients. These processes, however, do require protein synthesis. We asked how this fundamental conflict is resolved. Upon starvation, cells activate the Integrated Stress Response (ISR) and inhibit mammalian target of rapamycin complex 1 (mTORC1). The ISR inhibits protein translation through the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), whereas mTORC1 inhibition induces activation of the transcription factors TFEB/TFE3. We discovered that PPP1R15A (aka GADD34), a member of the protein phosphatase 1 complex (PP1) is a direct and early target of TFEB. GADD34 recruits PP1 to dephosphorylate eIF2 and thus fine-tunes protein synthesis to enable translation of the transcriptional program induced by starvation leading to a sustained autophagic flux.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Andrea Armirotti  

LAB HEAD: Andrea Armirotti

PROVIDER: PXD016149 | Pride | 2020-09-30

REPOSITORIES: Pride

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Dataset's files

Source:
Action DRS
CB_10Jan2018_TIGEM_DiBernardo_Sample001.wiff Wiff
CB_10Jan2018_TIGEM_DiBernardo_Sample001.wiff.scan Wiff
CB_10Jan2018_TIGEM_DiBernardo_Sample18.wiff Wiff
CB_10Jan2018_TIGEM_DiBernardo_Sample18.wiff.scan Wiff
CB_10Jan2019_TIGEM_DiBernardo-Proteins.mrkvw Other
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Publications

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 conflict  ...[more]

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