Figure 2

Interaction partners and substrates of Atg1, UNC-51 and Ulk1/2. In yeast, Atg1 directly interacts with Atg13 and Atg17-Atg29-Atg31; no autophagy-specific in vivo substrate of Atg1 has been identified yet. In nematodes, UNC-51 directly interacts with EPG-1; no autophagy-specific UNC-51 substrate is known. However, UNC-51 phosphorylates VAB-8 and UNC-14, two proteins involved in axonal trafficking of synaptic vesicles [25, 26, 28]. In insects, UNC-51/Atg1 binds and phosphorylates both Atg13 and the kinesin heavy chain adaptor protein UNC-76 that mediates synaptic vesicle transport [33]. In addition, the myosin light chain kinase named Sqa has been identified as autophagy-relevant UNC-51/Atg1 substrate [131]. In vertebrates, the UNC-51-like kinases 1 (Ulk1) and Ulk2 both directly interact with Atg13 and indirectly with FIP200 (a functional homolog of yeast Atg17). Ulk1/2 are able to phosphorylate Atg13 and FIP200, but the relevance for autophagy induction has not been determined yet. However, the Ulk1-dependent phosphorylation of Atg13 (at S318) does seem to be relevant for mitophagy [64]. The mammalian kinase ZIPK (a homolog of Drosophila Sqa), and the Beclin 1-interacting protein AMBRA1 have been identified as autophagy-relevant substrates of Ulk1 [131]. The synaptic proteins SynGAP and syntenin are known as neuron-specific interaction partners of Ulk1 [65], and syntenin-1 is directly phosphorylated by Ulk1 [66].