title: TBC1D14 regulates autophagy via the TRAPP complex and ATG9 traffic.
abstract: Macroautophagy requires membrane trafficking and remodelling to form the autophagosome and deliver its contents to lysosomes for degradation. We have previously identified the TBC domain-containing protein, TBC1D14, as a negative regulator of autophagy that controls delivery of membranes from RAB11-positive recycling endosomes to forming autophagosomes. In this study, we identify the TRAPP complex, a multi-subunit tethering complex and GEF for RAB1, as an interactor of TBC1D14. TBC1D14 binds to the TRAPP complex via an N-terminal 103 amino acid region, and overexpression of this region inhibits both autophagy and secretory traffic. TRAPPC8, the mammalian orthologue of a yeast autophagy-specific TRAPP subunit, forms part of a mammalian TRAPPIII-like complex and both this complex and TBC1D14 are needed for RAB1 activation. TRAPPC8 modulates autophagy and secretory trafficking and is required for TBC1D14 to bind TRAPPIII. Importantly, TBC1D14 and TRAPPIII regulate ATG9 trafficking independently of ULK1. We propose a model whereby TBC1D14 and TRAPPIII regulate a constitutive trafficking step from peripheral recycling endosomes to the early Golgi, maintaining the cycling pool of ATG9 required for initiation of autophagy.
authors.affiliation: Molecular Cell Biology of Autophagy Group, Francis Crick Institute, London, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lamb
authors.affiliation: Institute of Biochemistry II, Medical School Goethe University, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nühlen
authors.affiliation: Molecular Cell Biology of Autophagy Group, Francis Crick Institute, London, UK.
authors.forename: Delphine
authors.initials: D
authors.lastname: Judith
authors.affiliation: The Francis Crick Institute Mass Spectrometry Core Technology Platform Clare Hall Laboratories, Potters Bar, UK.
authors.forename: David
authors.initials: D
authors.lastname: Frith
authors.affiliation: The Francis Crick Institute Mass Spectrometry Core Technology Platform Clare Hall Laboratories, Potters Bar, UK.
authors.forename: Ambrosius P
authors.initials: AP
authors.lastname: Snijders
authors.affiliation: Institute of Biochemistry II, Medical School Goethe University, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Behrends
authors.affiliation: Molecular Cell Biology of Autophagy Group, Francis Crick Institute, London, UK Sharon.tooze@crick.ac.uk.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Tooze
mesh_terms: D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002460:Cell Line; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D011485:Protein Binding; D025941:Protein Interaction Mapping; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: C574794:ATG9A protein, human; D000071183:Autophagy-Related Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; C574472:TBC1D14 protein, human; C569828:TRAPPC8 protein, human; D033921:Vesicular Transport Proteins; C406327:transport protein particle, TRAPP; D020761:rab1 GTP-Binding Proteins
keywords: Autophagy; Membrane Trafficking; Rab proteins; TRAPP