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

• Published in: The Journal of cell biology Vol. 215; no. 6; pp. 841 - 856
• Main Authors: Nazio, Francesca, Carinci, Marianna, Valacca, Cristina, Bielli, Pamela, Strappazzon, Flavie, Antonioli, Manuela, Ciccosanti, Fabiola, Rodolfo, Carlo, Campello, Silvia, Fimia, Gian Maria, Sette, Claudio, Bonaldo, Paolo, Cecconi, Francesco
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 19.12.2016; The Rockefeller University Press
• Subjects: Autophagy; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Protein-1 Homolog - metabolism; Cellular biology; Down-Regulation; Endosomal Sorting Complexes Required for Transport - metabolism; HEK293 Cells; HeLa Cells; Homeostasis; Humans; Kinases; Lysine - metabolism; Models, Biological; Nedd4 Ubiquitin Protein Ligases; Proteasome Endopeptidase Complex - metabolism; Protein Binding; Protein Biosynthesis; Protein synthesis; Proteins; Proteolysis; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Time Factors; TOR Serine-Threonine Kinases - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.201605089

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.