The Atg1 complex, Atg9, and Vac8 recruit PI3K complex I to the pre-autophagosomal structure

Hitomi, Kanae; Kotani, Tetsuya; Noda, Nobuo N.; Kimura, Hirokazu; Nakatogawa, Hitoshi

doi:10.1083/jcb.202210017

Cited by 11 publications

(4 citation statements)

References 65 publications

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“…Atg38 is important for PI3KC3-C1 recruitment in yeast 41 , while we found that the human supercomplex assembles independently of the human Atg38 ortholog NRBF2. With respect to the third gap, the observation that PI3KC3-C1 binding to ULK1C triggers a rearrangement of ULK1C from a 2:1:1 to a 2:2:2 complex.…”

Section: Discussionmentioning

confidence: 68%

“…4b), and that the presence of ATG9 is not needed for the two complexes to interact. In yeast, the Atg1 complex (the yeast counterpart of human ULK1C) and PI3KC3-C1 are also reported to be in direct physical contact, which mediates the recruitment of PI3KC3-C1 to the phagophore initiation site in yeast 41 . The determinants of binding appear, however, to differ between yeast and humans.…”

Section: Discussionmentioning

confidence: 99%

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Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex

Chen

Ren

Cook

et al. 2023

Preprint

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The unc-51-like kinase protein kinase complex (ULK1C) and the class III phosphatidylinositol (PI) 3-kinase complex I (PI3KC3-C1) are the most upstream and central players in the initiation of macroautophagy. We found a direct physical interaction between the two complexes. The cryo-EM structures of the human ULK1C core and PI3KC3-C1 were determined at amino acid residue-level resolution, and used to interpret a moderate resolution structure of the ULK1C:PI3KC3-C1 supercomplex. The two complexes coassemble through extensive contacts between the FIP200 scaffold subunit of ULK1C and the VPS15 pseudokinase subunit of PI3KC3-C1. The presence of PI3KC3-C1 induces a rearrangement of ULK1C from a FIP200:ATG13:ULK1 2:1:1 to a 2:2:2 stoichiometry by dislocating an ATG13 loop (ATG13MR) from an inhibitory site on the dimeric FIP200 scaffold. This suggests a mechanism for the initiation of autophagy through PI3KC3-C1-induced dimerization of ULK1 as bound to FIP200, followed by an activating trans-autophosphorylation of ULK1.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex

Chen

Ren

Cook

et al. 2023

Preprint

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“…Vps34, and together with Vps15, Vps30, ATG14, and ATG38, forms PI3K complex I (PI3KCI) [ 131 , 133 , 134 , 135 ]. In yeast, PI3KCI constitutively binds to the vacuolar membrane protein Vac8 through ATG14 [ 136 ]. Upon autophagy initiation, ATG 1 recruits ATG9, ATG13, and ATG17-ATG31-ATG29 to assemble the ATG1 complex [ 137 , 138 , 139 ].…”

Section: Pi Scaffolding Complexes In Autophagymentioning

confidence: 99%

“…Upon autophagy initiation, ATG 1 recruits ATG9, ATG13, and ATG17-ATG31-ATG29 to assemble the ATG1 complex [ 137 , 138 , 139 ]. In an ATG1 kinase activity-dependent manner, PI3KCI associates with the ATG1 complex via the ATG38-ATG1 complex and Vps30-ATG9 interactions, anchoring PI3KC1 to the pre-autophagosomal structure for PI(3)P production [ 136 ]. A minor pool of PI(3)P is also generated from PI3KC2 in starvation-induced autophagy [ 22 ].…”

Section: Pi Scaffolding Complexes In Autophagymentioning

confidence: 99%

Regulation of Phosphoinositide Signaling by Scaffolds at Cytoplasmic Membranes

Wen,

Thapa,

Cryns

et al. 2023

Biomolecules

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Cytoplasmic phosphoinositides (PI) are critical regulators of the membrane–cytosol interface that control a myriad of cellular functions despite their low abundance among phospholipids. The metabolic cycle that generates different PI species is crucial to their regulatory role, controlling membrane dynamics, vesicular trafficking, signal transduction, and other key cellular events. The synthesis of phosphatidylinositol (3,4,5)-triphosphate (PI3,4,5P3) in the cytoplamic PI3K/Akt pathway is central to the life and death of a cell. This review will focus on the emerging evidence that scaffold proteins regulate the PI3K/Akt pathway in distinct membrane structures in response to diverse stimuli, challenging the belief that the plasma membrane is the predominant site for PI3k/Akt signaling. In addition, we will discuss how PIs regulate the recruitment of specific scaffolding complexes to membrane structures to coordinate vesicle formation, fusion, and reformation during autophagy as well as a novel lysosome repair pathway.

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Autophagy Activated by Atg1 Interacts With Atg9 Promotes Biofilm Formation and Resistance of Candida albicans

Huang,

Yu,

Liu

et al. 2024

Journal of Basic Microbiology

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Autophagy regulates the development of Candida albicans (C. albicans) biofilms and their sensitivity to antifungals. Atg1, a serine/threonine protein kinase, recruits autophagy‐related proteins for autophagosome formation. Atg9, the only transmembrane protein, is phosphorylated by Atg1 during autophagy. The specific roles of Atg1 and Atg9 in biofilm formation and resistance of C. albicans remain unclear. The study used RT‐qPCR and Western blotting to assess the correlation between Atg1, Atg9 and biofilm formation, XTT reduction assays to evaluate biofilm formation and antifungal resistance, commercial kits to detect reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and autophagy activity, transmission electron microscopy (TEM) to study the morphological changes, protein–protein interaction (PPI) analysis to analyze the interaction between Atg1 and Atg9. Results demonstrated that Atg1 and Atg9 were highly expressed in biofilms than planktonic cells. Biofilm formation, antifungal resistance, MMP and autophagy activity decreased and ROS increased in atg1Δ/Δ and atg9Δ/Δ. TORC1 inhibition with rapamycin rescued the reduced biofilm formation of atg1Δ/Δ and increased antifungal resistance of atg1Δ/Δ and atg9Δ/Δ. PPI analysis and TEM observation indicated that Atg1 interacted with Atg9, which was certified by RT‐qPCR and Western blotting. This study suggested that Atg1 interacts with Atg9, activates the autophagy regulating the formation and sensitivity of C. albicans biofilms.

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The Atg1 complex, Atg9, and Vac8 recruit PI3K complex I to the pre-autophagosomal structure

Cited by 11 publications

References 65 publications

Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex

Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex

Regulation of Phosphoinositide Signaling by Scaffolds at Cytoplasmic Membranes

Autophagy Activated by Atg1 Interacts With Atg9 Promotes Biofilm Formation and Resistance of Candida albicans

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