期刊
JOURNAL OF CELL BIOLOGY
卷 215, 期 6, 页码 841-856出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201605089
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资金
- Kraeftens Bekaempelse [KBVU R72-A4408]
- Lundbeckfonden [R167-2013-16100]
- Novo Nordisk UK Research Foundation [7559]
- Associazione Italiana per la Ricerca sul Cancro [IG2013]
- Fondazione Roma
- Associazione Italiana Sclerosi Multipla
- Fondazione Telethon [GGP14202]
- Ministero dell'Istruzione dell'Universita e della Ricerca (Fondo per gli Investimenti della Ricerca di Base Accordi di Programma)
- Ministero della Salute [GR-2011-02351643, GR2011]
- European Union [642295]
- Danmarks Grundforskningsfond
- Lundbeck Foundation [R167-2013-16100] Funding Source: researchfish
- Novo Nordisk Fonden [NNF13OC0007559] Funding Source: researchfish
- The Danish Cancer Society [R72-A4408] Funding Source: researchfish
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.
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