Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation

Claudio Sette, Francesca Nazio, Marianna Carinci, Cristina Valacca, Pamela Bielli, Flavie Strappazzon, Manuela Antonioli, Fabiola Ciccosanti, Carlo Rodolfo, Silvia Campello, Gian Maria Fimia, Paolo Bonaldo, Francesco Cecconi

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

67 Citazioni (Scopus)

Abstract

Autophagy is an intracellular degradation pathway whose levels are tightly controlled to secure cell homeostasis. Unc-51-like kinase 1 (ULK1) is a conserved serine-threonine kinase that plays a central role in the initiation of autophagy. Here, we report that upon autophagy progression, ULK1 protein levels are specifically down-regulated by the E3 ligase NEDD4L, which ubiquitylates ULK1 for degradation by the proteasome. However, whereas ULK1 protein is degraded, ULK1 mRNA is actively transcribed. Upon reactivation of mTOR-dependent protein synthesis, basal levels of ULK1 are promptly restored, but the activity of newly synthesized ULK1 is inhibited by mTOR. This prepares the cell for a new possible round of autophagy stimulation. Our results thus place NEDD4L and ULK1 in a key position to control oscillatory activation of autophagy during prolonged stress to keep the levels of this process under a safe and physiological threshold.
Lingua originaleEnglish
pagine (da-a)841-856
Numero di pagine16
RivistaTHE JOURNAL OF CELL BIOLOGY
Volume215
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Autophagy
  • Autophagy-Related Protein-1 Homolog
  • Cell Biology
  • Down-Regulation
  • Endosomal Sorting Complexes Required for Transport
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysine
  • Models, Biological
  • Nedd4 Ubiquitin Protein Ligases
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Biosynthesis
  • Proteolysis
  • RNA, Messenger
  • TOR Serine-Threonine Kinases
  • Time Factors
  • Ubiquitin-Protein Ligases
  • Ubiquitination

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