<scp>TBC</scp>1D14 regulates autophagy via the <scp>TRAPP</scp> complex and <scp>ATG</scp>9 traffic

<jats:title>Abstract</jats:title><jats:p>Macroautophagy requires membrane trafficking and remodelling to form the autophagosome and deliver its contents to lysosomes for degradation. We have previously identified the <jats:styled-content style="fixed-case">TBC</jats:styled-content> domain‐containing protein, <jats:styled-content style="fixed-case">TBC</jats:styled-content>1D14, as a negative regulator of autophagy that controls delivery of membranes from <jats:styled-content style="fixed-case">RAB</jats:styled-content>11‐positive recycling endosomes to forming autophagosomes. In this study, we identify the <jats:styled-content style="fixed-case">TRAPP</jats:styled-content> complex, a multi‐subunit tethering complex and <jats:styled-content style="fixed-case">GEF</jats:styled-content> for <jats:styled-content style="fixed-case">RAB</jats:styled-content>1, as an interactor of <jats:styled-content style="fixed-case">TBC</jats:styled-content>1D14. <jats:styled-content style="fixed-case">TBC</jats:styled-content>1D14 binds to the <jats:styled-content style="fixed-case">TRAPP</jats:styled-content> 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, <jats:styled-content style="fixed-case">TBC</jats:styled-content>1D14 and <jats:styled-content style="fixed-case">TRAPPIII</jats:styled-content> regulate <jats:styled-content style="fixed-case">ATG</jats:styled-content>9 trafficking independently of <jats:styled-content style="fixed-case">ULK</jats:styled-content>1. We propose a model whereby <jats:styled-content style="fixed-case">TBC</jats:styled-content>1D14 and <jats:styled-content style="fixed-case">TRAPPIII</jats:styled-content> regulate a constitutive trafficking step from peripheral recycling endosomes to the early Golgi, maintaining the cycling pool of <jats:styled-content style="fixed-case">ATG</jats:styled-content>9 required for initiation of autophagy.</jats:p>