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., Ciccosanti, F., Rodolfo, C., Campello, S., Fimia, G. M., Sette, C., Bonaldo, P., Cecconi, F., Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation, <<THE JOURNAL OF CELL BIOLOGY>>, 2016; 215 (6): 841-856. [doi:10.1083/jcb.201605089] [http://hdl.handle.net/10807/124732]

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

Sette, Claudio;
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.
Inglese
Nazio, F., Carinci, M., Valacca, C., Bielli, P., Strappazzon, F., Antonioli, M., Ciccosanti, F., Rodolfo, C., Campello, S., Fimia, G. M., Sette, C., Bonaldo, P., Cecconi, F., Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation, <<THE JOURNAL OF CELL BIOLOGY>>, 2016; 215 (6): 841-856. [doi:10.1083/jcb.201605089] [http://hdl.handle.net/10807/124732]
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