Rabs and GAPs in starvation-induced autophagy

Abstract

Formation of autophagosomes requires vesicular trafficking from virtually every subcellular compartment to the formation site. This traffic must be tightly regulated but also adaptable as different membrane compartments will contribute varying amounts of membrane, lipids and proteins to the forming autophagosome depending on the stimulus. In mammalian cells, efforts to understand how autophagosomes form have been focused on the role of Rab proteins in autophagy. Rab proteins provide specificity through their interaction with coat proteins, vesicle tethers and SNAREs. Recent data emerging from these studies have defined a subset of Rab proteins and their regulators, the RabGAPS (GTPase activating proteins) in both autophagosome formation and maturation. This review will focus on the role of a set of RabGAPs shown to regulate autophagy, in particular TBC1D14, and its interactors, RAB11 and TRAPPIII. Through our studies on TBC1D14, we have gained an understanding of the contribution of membrane from the recycling endosome, and the role of TRAPPIII in maintaining ATG (Autophagy protein) 9 trafficking in autophagosome formation.

Keywords: ATG9; Rab proteins; TBC domains; TRAPPIII; autophagosome; autophagy.

Figure 1.

Membrane compartments (omegasome, phagophore, autophagosome) and the early stage autophagy proteins ATG9, the protein kinase ULK complex, and the VPS34 PI3K (phosphatidylinositol 3-kinase) complex (called complex I) involved in autophagosome formation. Not shown is WIPI2 the PI3P (phosphatidylinositol 3-phosphate) effector, the ubiquitin-like conjugation complexes. LC3 is depicted on the phagophore but this could also be a GABARAP family member. Autophagosomes are depicted fusing with lysosomes to create an autolysosome but other endocytic compartments are also involved in the autophagosome maturation prior to fusion with the lysosome, include the recycling endosome.

Figure 2.

Scheme of human TBC1D14 and interactors. The TRAPPIII complexes which are specific to TRAPPII are colored green.

Figure 3.

Model for function of TBC1D14 and TRAPPIII in controlling ATG9 trafficking.