The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy.

Carinci, M., Testa, B., Bordi, M., Milletti, G., Bonora, M., Antonucci, L., et al. (2021). TFG binds LC3C to regulate ULK1 localization and autophagosome formation. EMBO JOURNAL, 40(10), e103563 [10.15252/embj.2019103563].

TFG binds LC3C to regulate ULK1 localization and autophagosome formation

Carinci, Marianna;Bordi, Matteo;Cecconi, Francesco
2021

Abstract

The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/06
English
ERGIC
LC3C
TFG
autophagy
Autophagosomes
Autophagy-Related Protein-1 Homolog
Blotting, Western
Fluorescent Antibody Technique
HEK293 Cells
HeLa Cells
Humans
Immunoprecipitation
Intracellular Signaling Peptides and Proteins
Microscopy, Electron, Transmission
Microtubule-Associated Proteins
Proteins
RNA Interference
Carinci, M., Testa, B., Bordi, M., Milletti, G., Bonora, M., Antonucci, L., et al. (2021). TFG binds LC3C to regulate ULK1 localization and autophagosome formation. EMBO JOURNAL, 40(10), e103563 [10.15252/embj.2019103563].
Carinci, M; Testa, B; Bordi, M; Milletti, G; Bonora, M; Antonucci, L; Ferraina, C; Carro, M; Kumar, M; Ceglie, D; Eck, F; Nardacci, R; le Guerroué, F; Petrini, S; Soriano, Me; Caruana, I; Doria, V; Manifava, M; Peron, C; Lambrughi, M; Tiranti, V; Behrends, C; Papaleo, E; Pinton, P; Giorgi, C; Ktistakis, Nt; Locatelli, F; Nazio, F; Cecconi, F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/303782
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