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Review
. 2020 Jan 3;432(1):123-134.
doi: 10.1016/j.jmb.2019.07.027. Epub 2019 Jul 25.

Recruitment and Activation of the ULK1/Atg1 Kinase Complex in Selective Autophagy

Eleonora Turco  1 , Dorotea Fracchiolla  2 , Sascha Martens  3
Affiliations
Review

Recruitment and Activation of the ULK1/Atg1 Kinase Complex in Selective Autophagy

Eleonora Turco et al. J Mol Biol. .

Abstract

Autophagy is a major cellular degradation pathway, which mediates the delivery of cytoplasmic cargo material into lysosomes. This is achieved by the specific sequestration of the cargo within double-membrane vesicles, the autophagosomes, which form de novo around this material. Autophagosome formation requires the action of a conserved set of factors, which act in hierarchical manner. The ULK1/Atg1 kinase complex is one of the most upstream acting components of the autophagy machinery. Here we discuss recent insights into the mechanisms of ULK1/Atg1 recruitment and activation at the cargo during selective autophagy. In particular, we will focus on the role of cargo receptors such as p62 and NDP52 during this process and discuss the emerging concept that cargo receptors act upstream of the autophagy machinery during cargo-induced selective autophagy.

Keywords: autophagosome; cargo receptor; protein kinase; quality control; signaling.

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Figures

Unlabelled Image
Graphical abstract
Fig. 1
Fig. 1
Mechanism of autophagy initiation during bulk (starvation-induced) and selective (cargo-induced) autophagy. (A) During starvation TORC1 is inhibited and the components of the ULK1/Atg1 complex become dephosphorylated. This event allows the assembly/recruitment of the ULK1/Atg1 complex at the site of autophagosome (AP) formation, in proximity of the ER or other membrane sources. ULK1/Atg1 clustering at the autophagosome formation site leads to its activation by auto-phosphorylation, which, in turn, triggers the recruitment of the autophagy machinery. This results in the formation of an autophagosome, which engulfs bulk material and receptor-bound cargo through the interaction of the receptor with ATG8-family proteins on the isolation membrane. (B) During selective autophagy, cytoplasmic cargo is recognized and bound by cargo receptors (directly or via ubiquitin), which induce autophagy by recruiting the ULK1/Atg1 complex to the cargo. Clustering of the ULK1/Atg1 complex at the cargo leads to its auto-activation and the recruitment of the autophagy machinery and membranes, which are necessary for the formation of an autophagosome, which subsequently specifically engulfs the cargo. A legend of shapes and colors used in the figure is shown below the panels.
Fig. 2
Fig. 2
Possible mechanism of ULK1/Atg1 complex activation by clustering during selective autophagy. The ULK1/Atg1 complex is recruited and clustered by the cargo receptor and positioned between the cargo and the vacuole/ER membrane. Under this condition, ULK1/Atg1 molecules are protected by the inhibitory signals of TORC1 and at the same time are close enough to each other for auto-phosphorylation and thus activation.
Fig. 3
Fig. 3
Schematic, scaled representation of FIP200 as scaffold for autophagy. The N-terminal and central region of the protein are involved in complex formation with ATG13, ATG101, and ULK1. In particular, ATG13 binds an LQFL motif (aa 582–585) in FIP200 N-terminus. The C-terminal region, including the claw domain (aa 1494–1594), is mainly involved in the interaction with cargo receptors. While NDP52 was shown to interact with a leucine zipper motif within the C-terminal region (1351–1567), the p62 binding pocket is located in FIP200 claw domain. It remains to be established if NDP52 could also bind the same p62 binding pocket and vice versa. The binding site for the ER-phagy receptor CCPG1 was also mapped to FIP200 C-terminal region (aa 1279–1594). Moreover, the FIP200 claw domain can also bind the TBK1 adaptor SINTBAD (aa 1567–1576).
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