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, Mukesh Kumar, Donatella Ceglie, Franziska Eck, Roberta Nardacci, Francois le Guerroué, Stefania Petrini, Maria E. Soriano, Ignazio Caruana, Valentina Doria, Maria Manifava, Camille Peron, Matteo LambrughiValeria Tiranti, Christian Behrends, Elena Papaleo, Paolo Pinton, Carlotta Giorgi, Nicholas T. Ktistakis, Franco Locatelli, Francesca Nazio, Francesco Cecconi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere103563
Pages (from-to)1-18
Number of pages18
JournalEMBO Journal
Volume40
Issue number10
DOIs
Publication statusPublished - May 17 2021

Keywords

  • autophagy
  • ERGIC
  • LC3C
  • TFG

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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