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Review
. 2013 Feb 1;9(2):124-37.
doi: 10.4161/auto.23323. Epub 2013 Jan 7.

The ULK1 complex: sensing nutrient signals for autophagy activation

Pui-Mun Wong  1 , Cindy Puente, Ian G Ganley, Xuejun Jiang
Affiliations
Review

The ULK1 complex: sensing nutrient signals for autophagy activation

Pui-Mun Wong et al. Autophagy. .

Abstract

The Atg1/ULK1 complex plays a central role in starvation-induced autophagy, integrating signals from upstream sensors such as MTOR and AMPK and transducing them to the downstream autophagy pathway. Much progress has been made in the last few years in understanding the mechanisms by which the complex is regulated through protein-protein interactions and post-translational modifications, providing insights into how the cell modulates autophagy, particularly in response to nutrient status. However, how the ULK1 complex transduces upstream signals to the downstream central autophagy pathway is still unclear. Although the protein kinase activity of ULK1 is required for its autophagic function, its protein substrate(s) responsible for autophagy activation has not been identified. Furthermore, examples of potential ULK1-independent autophagy have emerged, indicating that under certain specific contexts, the ULK1 complex might be dispensable for autophagy activation. This raises the question of how the autophagic machinery is activated independent of the ULK1 complex and what are the biological functions of such noncanonical autophagy pathways.

Keywords: AMPK; Atg1; MTOR; kinase; regulation.

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Figures

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Figure 1. Atg1 and its homologous proteins in different organisms. The figure is a schematic representation of Atg1 (yeast), UNC-51 (C. elegans) and ULKs (mice). These proteins share high sequence identity and/or similarity mainly in the kinase domains. Significant similarity is also seen in the tail of Atg1, UNC-51, ULK1, and ULK2, defining a C-terminal domain of 150–250 amino acids. Overall sequence identity to mouse ULK1 as calculated by ClustalW is shown on the left-hand side.
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Figure 2. Regulation of the Atg1 complex in yeast and the ULK1 complex in mammalian cells. In yeast, one model suggests that TORC1 dictates autophagy activation through regulating Atg1 complex formation: TORC1 phosphorylates Atg13 under nutrient-rich conditions, preventing complex formation (for simplicity, only Atg1, Atg13, and Atg17 are shown here); upon starvation, TORC1 is inactivated, thus the inhibitory phosphorylation on Atg13 is removed, triggering complex formation with Atg1 and Atg17. However, recent reports indicate that the Atg1-Atg13-Atg17 complex is constitutively formed in yeast. In mammals, the ULK1 complex is stable even under nutrient-rich conditions. Inhibitory phosphorylation by MTOR on ULK1 and ATG13 prevents complex activation, likely through a specific conformational change of the ULK1 complex. A red “P” indicates inhibitory phosphorylation, whereas blue “P” indicates potential activating phosphorylation.
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Figure 3. Domain structure and posttranslational modifications on ULK1. (A) ULK1 contains an N-terminal kinase domain, a C-terminal domain (CTD) that is conserved with the yeast and C. elegans counterparts, and a serine/proline-rich region in between that is the site for many post-translational modification events. ATG13 and RB1CC1/FIP200 interact with ULK1 through its CTD. The mapped interaction sites with members of the LC3 family and AMPK are indicated. The site of interaction with RPTOR is unresolved, as its interaction with either the kinase domain or the serine/proline-rich domain has been reported. (B) Post-translationally modified residues on ULK1. As many as 30 phosphorylation events have been reported for ULK1. For brevity, only events that have been experimentally verified are listed in the table. Similarly, only the two experimentally verified acetylation sites are listed in the table.
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Figure 4. The ULK1 complex integrates upstream nutrient and energy signals to coordinate the induction of autophagy. The nutrient-sensing pathways for growth factors, amino acids and energy converge on ULK1 through unique post-translational modifications, which regulate the activity of this autophagy-induction complex. MTOR inhibits the induction of autophagy through regulation of the ULK1 complex, which undergoes global dephosphorylation upon starvation. The acetyltransferase TIP60, which is regulated by the growth factor-sensitive kinase GSK3B, catalyzes acetylation of ULK1 to bolster its kinase activity. The energy-sensing kinase AMPK can promote autophagy through inhibition of MTOR and may fine-tune the autophagic response through regulation of the ULK1 complex as well. Dark blue arrows indicate events that promote autophagy, while light blue arrows indicate events that are inhibitory to autophagy. The gray arrow between AMPK and ULK1 indicates the possibility that AMPK phosphorylation of ULK1 exerts multiple regulatory effects on ULK1.
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Figure 5. ULK1-dependent and -independent autophagy . The role of the ULK1 complex in amino acid starvation-induced autophagy is well established. There are, however, triggers for autophagy that can feed into the downstream machinery to trigger the autophagic cascade and LC3 conjugation in a ULK1 complex-independent manner. Because the ULK1 complex can directly communicate with the ATG5 complex and likely functions upstream of the PIK3C3 complex, triggers of ULK1-independent autophagy pathways might also signal through both the ATG5 and PIK3C3 complexes, as depicted in the figure.
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References

    1. Chen Y, Klionsky DJ. The regulation of autophagy - unanswered questions. J Cell Sci. 2011;124:161–70. doi: 10.1242/jcs.064576. - DOI - PMC - PubMed
    1. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147:728–41. doi: 10.1016/j.cell.2011.10.026. - DOI - PubMed
    1. Todde V, Veenhuis M, van der Klei IJ. Autophagy: principles and significance in health and disease. Biochim Biophys Acta. 2009;1792:3–13. doi: 10.1016/j.bbadis.2008.10.016. - DOI - PubMed
    1. Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27:107–32. doi: 10.1146/annurev-cellbio-092910-154005. - DOI - PubMed
    1. Ganley IG, Wong PM, Gammoh N, Jiang X. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol Cell. 2011;42:731–43. doi: 10.1016/j.molcel.2011.04.024. - DOI - PMC - PubMed

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