A molecular perspective of mammalian autophagosome biogenesis

Mercer, Thomas J.; Gubaš, Andrea; Tooze, Sharon A.

doi:10.1074/jbc.r117.810366

Cited by 236 publications

(220 citation statements)

References 127 publications

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“…In mammals (Bento et al, 2016), these include the ULK1 (unc-51 like autophagy activating kinase 1) protein kinase complex, the class III phosphatidylinositol 3-kinase complexes (PI3KC3), the phosphatidylinositol 3-phosphate (PI(3)P)-sensing WIPI proteins, the lipid transporter ATG2 (autophagy related 2), the integral membrane protein ATG9, the ubiquitin-like ATG8 proteins, machinery for conjugating ATG8 protein to lipid membranes, the autophagy adaptors that connect substrates to the ULK1 complex and to ATG8 proteins, and TBK1 (TANK binding kinase 1), which phosphoregulates autophagy adaptors. The mechanisms by which these protein complexes orchestrate autophagosome initiation, growth, closure, and delivery to the lysosome are being actively sought (Hurley and Young, 2017;Mercer et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer

Shi

Yokom

Wang

et al. 2019

Preprint

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The human ULK complex consists of ULK1/2, FIP200, ATG13, and ATG101. We found that the FIP200 N-terminal domain is a C-shaped dimer that binds directly to a single ATG13 molecule and serves as the organizing hub of the complex. AbstractThe autophagy-initiating human ULK complex consists of the kinase ULK1/2, FIP200, ATG13, and ATG101. Hydrogen-deuterium exchange mass spectrometry was used to map their mutual interactions. The N-terminal 640 residues (NTD) of FIP200 interact with the C-terminal IDR of ATG13. Mutations in these regions abolish their interaction. Negative stain electron microscopy (EM) and multiangle light scattering showed that FIP200 is a dimer whilst a single molecule each of the other subunits is present. The FIP200 NTD is flexible in the absence of ATG13, but in its presence adopts the shape of the letter C ~20 nm across. The ULK1 EAT domain interacts loosely with the NTD dimer, while the ATG13-ATG101 HORMA dimer does not contact the NTD. Cryo-EM of the NTD dimer revealed a structure similarity to the scaffold domain of TBK1, suggesting an evolutionary similarity between the autophagy initiating TBK1 kinase and the ULK1 kinase complex.

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Section: Introductionmentioning

confidence: 99%

ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer

Shi

Yokom

Wang

et al. 2019

Preprint

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“…A recent article in Genes & Development by Ruan et al provides new insights into glucagon regulation of hepatic autophagy during nutrient deprivation. The findings demonstrate a novel function for the protein modification of O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) in the regulation of starvation‐induced autophagy through an effect on unc‐51‐like kinase 1 (ULK1), which initiates the process of phagophore formation …”

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confidence: 99%

“…The findings demonstrate a novel function for the protein modification of O-linked β-N-acetylglucosamine (O-GlcNAc) in the regulation of starvation-induced autophagy through an effect on unc-51-like kinase 1 (ULK1), which initiates the process of phagophore formation. (3) In times of adequate nutrient supply, glucoseinduced insulin and amino acids trigger mammalian target of rapamycin activation to suppress autophagy. With nutrient insufficiency, low serum glucose leads to pancreatic release of the counterregulatory hormone glucagon, which increases hepatocyte autophagy.…”

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confidence: 99%

A Novel Mechanism of Starvation‐Stimulated Hepatic Autophagy: Calcium‐Induced O‐GlcNAc‐Dependent Signaling

Shen

Czaja

2018

Hepatology

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Two central functions of the lysosomal degradative pathway of macroautophagy (hereafter referred to as autophagy) are to provide cells with metabolic substrates for energy generation in times of limited nutrients and act as a quality control mechanism to remove damaged or aged cellular components. Recent investigations have demonstrated that both functions regulate normal hepatic physiology and when impaired contribute to the pathophysiology of liver disease. The full spectrum of autophagy's metabolic functions in the liver has recently begun to be defined. This article is protected by copyright. All rights reserved.

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“…While ULK1/2 activation is typically a prerequisite for LC3 processing by the ubiquitin-like conjugation system on the forming autophagosome 17 , several upstream ULK1/2-dependent molecular events are essential to initiate autophagosome formation 39,40 ( Supplementary Fig. 2c).…”

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confidence: 99%

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

Tsang

Posimo

Gudiel

et al. 2019

Preprint

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Targeting aberrant kinase activity in cancer relies on unmasking cellular inputs such as growth factors, nutrients, and metabolites that contribute to cancer initiation and progression 1 . While the transition metal copper (Cu) is an essential nutrient that is traditionally viewed as a static cofactor within enzyme active sites 2 , a newfound role for Cu as a modulator of kinase signaling is emerging 3,4 . We discovered that Cu is required for the activity of the autophagic kinases ULK1/2 through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt Cu-binding reduced ULK1/2-dependent signaling and autophagosome complex formation. Elevated intracellular Cu levels are associated with starvation induced autophagy and sufficient to enhance ULK1 kinase activity and in turn autophagic flux. Targeting autophagy machinery is a promising therapeutic strategy in cancers 5 , but is limited by the absence of potent inhibitors and the emergence of resistance. The growth and survival of lung tumors driven by KRAS G12D is diminished in the absence of Ctr1, depends on ULK1 Cu-binding, and is associated with reduced autophagy levels and signaling. These findings suggest a new molecular basis for exploiting Cu-chelation therapy to forestall autophagy signaling to limit proliferation and survival in cancer.By default, the dynamic and adaptive nature of signaling networks allows them to respond and, in some cases, sense extracellular and intracellular inputs 6 . While growth factors, nutrients, and metabolites are well-appreciated regulators of cell proliferation, the contribution of transition metals to cellular processes that support proliferation and contribute to malignant transformation are understudied. The transition metal copper (Cu) is essential for a diverse array of biological processes from cellular proliferation, neuropeptide processing, free radical detoxification, and

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A molecular perspective of mammalian autophagosome biogenesis

Cited by 236 publications

References 127 publications

ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer

ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer

A Novel Mechanism of Starvation‐Stimulated Hepatic Autophagy: Calcium‐Induced O‐GlcNAc‐Dependent Signaling

Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma

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