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. 2012 Mar 13;10(1):7.
doi: 10.1186/1478-811X-10-7.

The incredible ULKs

Sebastian Alers  1 , Antje S Löffler, Sebastian Wesselborg, Björn Stork
Affiliations

The incredible ULKs

Sebastian Alers et al. Cell Commun Signal. .

Abstract

Macroautophagy (commonly abbreviated as autophagy) is an evolutionary conserved lysosome-directed vesicular trafficking pathway in eukaryotic cells that mediates the lysosomal degradation of intracellular components. The cytoplasmic cargo is initially enclosed by a specific double membrane vesicle, termed the autophagosome. By this means, autophagy either helps to remove damaged organelles, long-lived proteins and protein aggregates, or serves as a recycling mechanism for molecular building blocks. Autophagy was once invented by unicellular organisms to compensate the fluctuating external supply of nutrients. In higher eukaryotes, it is strongly enhanced under various stress conditions, such as nutrient and growth factor deprivation or DNA damage. The serine/threonine kinase Atg1 was the first identified autophagy-related gene (ATG) product in yeast. The corresponding nematode homolog UNC-51, however, has additional neuronal functions. Vertebrate genomes finally encode five closely related kinases, of which UNC-51-like kinase 1 (Ulk1) and Ulk2 are both involved in the regulation of autophagy and further neuron-specific vesicular trafficking processes. This review will mainly focus on the vertebrate Ulk1/2-Atg13-FIP200 protein complex, its function in autophagy initiation, its evolutionary descent from the yeast Atg1-Atg13-Atg17 complex, as well as the additional non-autophagic functions of its components. Since the rapid nutrient- and stress-dependent cellular responses are mainly mediated by serine/threonine phosphorylation, it will summarize our current knowledge about the relevant upstream signaling pathways and the altering phosphorylation status within this complex during autophagy induction.

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Figures

Figure 1
Figure 1
Evolutionary descent of the vertebrate Ulk1/2-Atg13-FIP200 complex. (A) In the "baker's yeast" species Saccharomyces cerevisiae, the protein kinase Atg1 is found in a large protein complex that comprises Atg13 and Atg17-Atg29-Atg31, once autophagy is initiated. Under starvation conditions, the hypophosphorylated protein Atg13 induces self-association of Atg1, which strongly enhances its kinase activity. S. cerevisiae additionally expresses Atg11, a scaffolding protein that is involved in the fungi-specific Cvt pathway. (B) The closely related "fission yeast" species Saccharomyces pombe expresses Atg1 and Atg13. Both proteins are essential for autophagy induction [79]. It additionally possesses a homolog of yeast Atg17 and a putative homolog of yeast Atg11 (Taz1IF1) [51,78]. However, Taz1IF1 shows great similarity to vertebrate FIP200 [51]. The protein Mug66 has been assigned as a putative homolog of vertebrate Atg101 [51]. The molecular details of autophagy induction have not been addressed yet. (C) The nematode Caenorhabditis elegans expresses an Atg1 homolog (UNC-51) and an interacting Atg13 homolog (EPG-1) that both are essential for autophagy induction [24,32], while the phosphorylation of EPG-1 by UNC-51 has not been determined yet. The nematode genome contains a homolog of both FIP200 (T08A9.1; assigned as atg-11) and Atg101 (Y69A2AR.7); their role in autophagy has not been addressed. (D) In the fruit fly species Drosophila melanogaster, dAtg1 binds and phosphorylates dAtg13. In contrast to yeast, the dAtg1-dependent phosphorylation of Atg13 is greatest under autophagic condition. The composition of the dAtg1-dAtg13 complex is not affected by the nutrient status [34,35,37]. The Drosophila genome contains a FIP200 homolog (CG1347) and an Atg101 homolog (CG7053). The involvement of the respective gene products has not been addressed. (E) Vertebrate species possess a large protein complex, comprising Ulk1 or Ulk2, Atg13, FIP200 and Atg101, whose composition is unaffected by the nutrient status [53-56,68,75,76,85]. In mammals, mTORC1 associates with this complex under normal growth conditions and phosphorylates Ulk1/2 and Atg13, thereby inhibiting Ulk1/2 kinase activity [55]. Active Ulk1/2 autophosphorylates and is able to phosphorylate both Atg13 and FIP200, but the relevance for autophagy induction has not been determined yet.
Figure 2
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].
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