Autophagy is important in the basal or stress-induced clearance of bulk cytosol, damaged organelles, pathogens and selected proteins by specific vesicles, the autophagosomes. Following mTOR (mammalian target of rapamycin) inhibition, autophagosome formation is primed by the ULK1 and the beclin-1-Vps34-AMBRA1 complexes, which are linked together by a scaffold platform, the exocyst. Although several regulative steps have been described along this pathway, few targets of mTOR are known, and the cross-talk between ULK1 and beclin 1 complexes is still not fully understood. We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.

Nazio, F., Strappazzon, F., Antonioli, M., Bielli, P., Cianfanelli, V., Bordi, M., et al. (2013). mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. NATURE CELL BIOLOGY, 15(4), 406-416 [10.1038/ncb2708].

mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6

Nazio, F;Antonioli, M;BIELLI, PAMELA;PIACENTINI, MAURO;CECCONI, FRANCESCO
2013-01-01

Abstract

Autophagy is important in the basal or stress-induced clearance of bulk cytosol, damaged organelles, pathogens and selected proteins by specific vesicles, the autophagosomes. Following mTOR (mammalian target of rapamycin) inhibition, autophagosome formation is primed by the ULK1 and the beclin-1-Vps34-AMBRA1 complexes, which are linked together by a scaffold platform, the exocyst. Although several regulative steps have been described along this pathway, few targets of mTOR are known, and the cross-talk between ULK1 and beclin 1 complexes is still not fully understood. We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.
2013
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/06 - ANATOMIA COMPARATA E CITOLOGIA
English
Con Impact Factor ISI
Real-Time Polymerase Chain Reaction; TOR Serine-Threonine Kinases; Autophagy; HeLa Cells; Intracellular Signaling Peptides and Proteins; Humans; Immunoprecipitation; RNA, Small Interfering; Protein-Serine-Threonine Kinases; Protein Binding; RNA, Messenger; TNF Receptor-Associated Factor 6; Blotting, Western; Phosphorylation; Adaptor Proteins, Signal Transducing; Cells, Cultured; Ubiquitination; Immunoenzyme Techniques
Nazio, F., Strappazzon, F., Antonioli, M., Bielli, P., Cianfanelli, V., Bordi, M., et al. (2013). mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. NATURE CELL BIOLOGY, 15(4), 406-416 [10.1038/ncb2708].
Nazio, F; Strappazzon, F; Antonioli, M; Bielli, P; Cianfanelli, V; Bordi, M; Gretzmeier, C; Dengjel, J; Piacentini, M; Fimia, G; Cecconi, F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/91451
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