Atg4 proteolytic activity can be inhibited by Atg1 phosphorylation

Sánchez, Jana; Kriegenburg, Franziska; Rohringer, Sabrina; Schuschnig, Martina; Gómez-Sánchez, Rubén; Zens, Bettina; Abreu, Susana; Hardenberg, Ralph; Hollenstein, David Maria; Gao, Jieqiong; Ungermann, Christian; Martens, Sascha; Kraft, Claudine; Reggiori, Fulvio

doi:10.1038/s41467-017-00302-3

Cited by 69 publications

(76 citation statements)

References 44 publications

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“…Spatial and temporal regulation of recruitment and dissociation of LC3 family proteins to and from autophagosomes is achieved through regulation of ATG4 activity [13][14][15][16][17]. Spatial and temporal regulation of recruitment and dissociation of LC3 family proteins to and from autophagosomes is achieved through regulation of ATG4 activity [13][14][15][16][17].…”

Section: Discussionmentioning

confidence: 99%

“…Spatial and temporal regulation of recruitment and dissociation of LC3 family proteins to and from autophagosomes is achieved through regulation of ATG4 activity [13][14][15][16][17]. This regulation is achieved through the phosphorylation and dephosphorylation of ATG4 itself [15,16] and the phosphorylation of LC3s by TBK1. This suggests that LC3-II conjugated to autophagosomes is protected from premature de-lipidation by a timely regulatory mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…LC3 proteins undergo two processing steps, (i) an initial proteolytic cleavage of the peptide bond responsible for the conversion of pro-LC3 to active LC3 (LC3-I) and (ii) the subsequent cleavage of the amide bond for de-lipidation of LC3-II from autophagosomes to regenerate a free cytosolic LC3 pool. Phosphorylation of ATG4B at S383/392 increases its protease activity [14], especially during the LC3 de-lipidation phase, whereas ULK1-mediated phosphorylation of ATG4B at S316 (in humans) [15] or at S307 (in yeast) [16] reduces pro-LC3 binding and C-terminal tail cleavage. Among the four mammalian paralogs of ATG4, ATG4B is the most active protease followed by ATG4A and ATG4C/D, which exhibit minimal protease activity [10,11].…”

Section: Introductionmentioning

confidence: 99%

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TBK1‐mediated phosphorylation of LC3C and GABARAP‐L2 controls autophagosome shedding by ATG4 protease

et al. 2019

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Autophagy is a highly conserved catabolic process through which defective or otherwise harmful cellular components are targeted for degradation via the lysosomal route. Regulatory pathways, involving post-translational modifications such as phosphorylation, play a critical role in controlling this tightly orchestrated process. Here, we demonstrate that TBK1 regulates autophagy by phosphorylating autophagy modifiers LC3C and GABARAP-L2 on surfaceexposed serine residues (LC3C S93 and S96; GABARAP-L2 S87 and S88). This phosphorylation event impedes their binding to the processing enzyme ATG4 by destabilizing the complex. Phosphorylated LC3C/GABARAP-L2 cannot be removed from liposomes by ATG4 and are thus protected from ATG4-mediated premature removal from nascent autophagosomes. This ensures a steady coat of lipidated LC3C/GABARAP-L2 throughout the early steps in autophagosome formation and aids in maintaining a unidirectional flow of the autophagosome to the lysosome. Taken together, we present a new regulatory mechanism of autophagy, which influences the conjugation and de-conjugation of LC3C and GABARAP-L2 to autophagosomes by TBK1-mediated phosphorylation.

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Section: Discussionmentioning

confidence: 99%

“…Spatial and temporal regulation of recruitment and dissociation of LC3 family proteins to and from autophagosomes is achieved through regulation of ATG4 activity [13][14][15][16][17]. This regulation is achieved through the phosphorylation and dephosphorylation of ATG4 itself [15,16] and the phosphorylation of LC3s by TBK1. This suggests that LC3-II conjugated to autophagosomes is protected from premature de-lipidation by a timely regulatory mechanism.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TBK1‐mediated phosphorylation of LC3C and GABARAP‐L2 controls autophagosome shedding by ATG4 protease

et al. 2019

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“…However, overall expression of ATG4 proteins in healthy cells is quite stable and ubiquitous. ATG4B undergoes several types of post-translational modifications under multiple conditions [60], including ubiquitination [59], O-GlcNAcylation [61], S-nitrosylation [62], caspase-mediated proteolysis [42,63], redox mechanisms [64][65][66], and phosphorylation [12][13][14][15]67].…”

Section: Atg4b As Drug Targetmentioning

confidence: 99%

“…It is emerging that the activity of ATG4B is tightly controlled by post-translational modifications, including phosphorylation mediated by ATG1/ULK1 [12,13], AKT1 [14], and serine/threonine protein kinase MST4 [15]. For instance, phosphorylation of ATG4B by ULK1 on serine 316 results in a reduction of LC3-II hydrolysis [12], allowing the autophagosome to close before premature deconjugation of LC-II from the autophagosome membrane.…”

Section: Introductionmentioning

confidence: 99%

On ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns

Agrotis

Ketteler

2019

Cells

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Autophagy is an evolutionary conserved stress survival pathway that has been shown to play an important role in the initiation, progression, and metastasis of multiple cancers; however, little progress has been made to date in translation of basic research to clinical application. This is partially due to an incomplete understanding of the role of autophagy in the different stages of cancer, and also to an incomplete assessment of potential drug targets in the autophagy pathway. While drug discovery efforts are on-going to target enzymes involved in the initiation phase of the autophagosome, e.g., unc51-like autophagy activating kinase (ULK)1/2, vacuolar protein sorting 34 (Vps34), and autophagy-related (ATG)7, we propose that the cysteine protease ATG4B is a bona fide drug target for the development of anti-cancer treatments. In this review, we highlight some of the recent advances in our understanding of the role of ATG4B in autophagy and its relevance to cancer, and perform a critical evaluation of ATG4B as a druggable cancer target.

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Shedding Light on the Role of Phosphorylation in Plant Autophagy

Liao

Zheng

et al. 2022

FEBS Letters

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Autophagy is a highly conserved quality control process that maintains cellular health by eliminating deleterious cargoes. Compared with the extensive studies in yeast and mammalian models, the molecular details and significance of post-translational modifications (PTMs) in the autophagy process in plants remain less well defined. In this review, we discuss recent progress in our understanding of phosphorylation, one of the most extensively studied PTMs, in the regulation of autophagosome biogenesis and autophagic degradation in plants. Based on the plant mass spectrometric database, we summarize the experimentally verified phosphorylation sites of the core autophagy machinery in plants. Furthermore, we put forward several approaches to test the roles of phosphorylation in the regulation of plant autophagy.

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Atg4 proteolytic activity can be inhibited by Atg1 phosphorylation

Cited by 69 publications

References 44 publications

TBK1‐mediated phosphorylation of LC3C and GABARAP‐L2 controls autophagosome shedding by ATG4 protease

TBK1‐mediated phosphorylation of LC3C and GABARAP‐L2 controls autophagosome shedding by ATG4 protease

On ATG4B as Drug Target for Treatment of Solid Tumours—The Knowns and the Unknowns

Shedding Light on the Role of Phosphorylation in Plant Autophagy

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