TFG binds LC3C to regulate ULK1 localization and autophagosome formation
Marianna Carinci, Beatrice Testa, Matteo Bordi, Giacomo Milletti, Massimo Bonora, Laura Antonucci, Caterina Ferraina, Marta Carro-Alvarellos, Mukesh Kumar, Donatella Ceglie, Franziska Eck, Roberta Nardacci, François Le Guerroué, Stefania Petrini, María Eugenia Soriano, Ignazio Caruana, Valentina Doria, Maria Manifava, Camille Peron, Matteo Lambrughi, Valeria Tiranti, Christian Behrends, Elena Papaleo, Paolo Pinton, Carlotta Giorgi, Nicholas T. Ktistakis, Franco Locatelli, Francesca Nazio, Francesco Cecconi
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. TFG (Trk‐fused gene) is a resident protein of the interface between endoplasmic reticulum (ER) and ER‐Golgi intermediate compartment (ERGIC), coordinating the distribution of COPII vesicles between the two compartments. This study reveals that, upon starvation‐induced autophagy, TFG regulates autophagosome formation in mammalian cells by acting on the ULK1‐LC3C axis. Trk‐fused gene (TFG) acts as a molecular scaffold linking the early secretory pathway and autophagy in mammalian cells.