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.

Nazio, F., Carinci, M., Valacca, C., Bielli, P., Strappazzon, F., Antonioli, M., et al. (2016). Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation. THE JOURNAL OF CELL BIOLOGY, 215(6), 841-856 [10.1083/jcb.201605089].

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

NAZIO, FRANCESCA;CARINCI, MARIANNA;BIELLI, PAMELA;ANTONIOLI, MANUELA;RODOLFO, CARLO;CAMPELLO, SILVIA;SETTE, CLAUDIO;CECCONI, FRANCESCO
2016

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/06
English
Con Impact Factor ISI
Nazio, F., Carinci, M., Valacca, C., Bielli, P., Strappazzon, F., Antonioli, M., et al. (2016). Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation. THE JOURNAL OF CELL BIOLOGY, 215(6), 841-856 [10.1083/jcb.201605089].
Nazio, F; Carinci, M; Valacca, C; Bielli, P; Strappazzon, F; Antonioli, M; Ciccosanti, F; Rodolfo, C; Campello, S; Fimia, G; Sette, C; Bonaldo, P; Cecconi, F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/172692
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