Autophagy-regulating protease Atg4: structure, function, regulation and inhibition

Maruyama, Tatsuro; Noda, Nobuo N.

doi:10.1038/ja.2017.104

Cited by 132 publications

(103 citation statements)

References 71 publications

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“…Atg4 is a cysteine protease of Clan CA and family C54 that is a crucial for both Atg8-PE conjugation and subsequent delipidation [61]. Atg4 was first identified in yeast by Lang et al [46], who demonstrated that this protein was essential for the process of delivering the autophagic vesicles to the vacuole lumen in S. cerevisiae.…”

Section: Discussionmentioning

confidence: 99%

Biological functions of the autophagy-related proteins Atg4 and Atg8 in Cryptococcus neoformans

et al. 2020

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Autophagy is a mechanism responsible for intracellular degradation and recycling of macromolecules and organelles, essential for cell survival in adverse conditions. More than 40 autophagy-related (ATG) genes have been identified and characterized in fungi, among them ATG4 and ATG8. ATG4 encodes a cysteine protease (Atg4) that plays an important role in autophagy by initially processing Atg8 at its C-terminus region. Atg8 is a ubiquitin-like protein essential for the synthesis of the double-layer membrane that constitutes the autophagosome vesicle, responsible for delivering the cargo from the cytoplasm to the vacuole lumen. The contributions of Atg-related proteins in the pathogenic yeast in the genus Cryptococcus remain to be explored, to elucidate the molecular basis of the autophagy pathway. In this context, we aimed to investigate the role of autophagy-related proteins 4 and 8 (Atg4 and Atg8) during autophagy induction and their contribution with non-autophagic events in C. neoformans. We found that Atg4 and Atg8 are conserved proteins and that they interact physically with each other. ATG gene deletions resulted in cells sensitive to nitrogen starvation. ATG4 gene disruption affects Atg8 degradation and its translocation to the vacuole lumen, after autophagy induction. Both atg4 and atg8 mutants are more resistant to oxidative stress, have an impaired growth in the presence of the cell wall-perturbing agent Congo Red, and are sensitive to the proteasome inhibitor bortezomib (BTZ). By that, we conclude that in C. neoformans the autophagy-related proteins Atg4 and Atg8 play an important role in the autophagy pathway; which are required for autophagy regulation, maintenance of amino acid levels and cell adaptation to stressful conditions. OPEN ACCESS Citation: Roberto TN, Lima RF, Pascon RC, Idnurm A, Vallim MA (2020) Biological functions of the autophagy-related proteins Atg4 and Atg8 in Cryptococcus neoformans. PLoS ONE 15(4): e0230981. https://doi.org/10.Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files.individuals [2]. The therapy against cryptococcosis requires a long period of treatment with antifungal drugs used singly or in combination, some of which are highly toxic to the patient [3]. Due to the long period of clinical treatment, some reports indicate that fungi of the genus Cryptococcus may have a high potential to antifungal resistance, which could explain the therapeutic failures and recurrent relapses in the patients with cryptococcosis [4]. Thus, further studies for new strategies that contribute with the knowledge about the treatment of this mycosis, leading to the deficiency of growth, multiplication, and/or survival of the fungus in the host are of great importance. In this context, the elucidation of autophagic pathways in fungi may provide new insights into the relationship established during the infection process between pathogen and host [5].Autophagy is an intracellular mechanism responsible for degradation and recycling of macr...

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Section: Discussionmentioning

confidence: 99%

Biological functions of the autophagy-related proteins Atg4 and Atg8 in Cryptococcus neoformans

et al. 2020

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“…In the latter, the inhibition is produced by the formation of a disulfide bond and very low redox potentials are required for its activation, which is mediated by the cytosolic thioredoxin TRXh1 [118]. The importance of a functional ATG4 in autophagy is supported by data showing that when ATG4 activity is increased by either phosphorylation or glycosylation, autophagy is activated, and when it is reduced by ubiquitination autophagy is inhibited [119].…”

Section: Ros Levelsmentioning

confidence: 99%

Linking Autophagy to Abiotic and Biotic Stress Responses

Signorelli

Tarkowski

Ende

et al. 2019

Trends in Plant Science

225

176

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Autophagy is a process in which cellular components are delivered to lytic vacuoles to be recycled and has been demonstrated to promote abiotic/biotic stress tolerance. Here, we review how the responses triggered by stress conditions can affect autophagy and its signaling pathways. Besides the role of SNF-related kinase 1 (SnRK1) and TOR kinases in the regulation of autophagy, abscisic acid (ABA) and its signaling kinase SnRK2 have emerged as key players in the induction of autophagy under stress conditions. Furthermore, an interplay between reactive oxygen species (ROS) and autophagy is observed, ROS being able to induce autophagy and autophagy able to reduce ROS production. We also highlight the importance of osmotic adjustment for the successful performance of autophagy and discuss the potential role of GABA in plant survival and ethylene (ET)-induced autophagy.

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“…Redox conditions within mammalian cells have been shown to directly regulate the activity of autophagy core proteins, including the cysteine protease ATG4 and the autophagy receptor p62 (160,195). In mammals, four homologs of ATG4 with distinct cysteine protease activities have been identified: ATG4A/ autophagin-2, ATG4B/autophagin-1, ATG4C/autophagin-3, and ATG4D/autophagin-4 (139). ATG4 catalyzes cleavage of LC3 to expose a COOH-terminal glycine residue that ultimately leads to conjugation with PE (LC3-II-PE).…”

Section: Autophagy and Oxidant Exposurementioning

confidence: 99%

Oxidative stress, autophagy and airway ion transport

O’Grady

2019

American Journal of Physiology-Cell Physiology

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Mucociliary clearance is critically important in protecting the airways from infection and from the harmful effects of smoke and various inspired substances known to induce oxidative stress and persistent inflammation. An essential feature of the clearance mechanism involves regulation of the periciliary liquid layer on the surface of the airway epithelium, which is necessary for normal ciliary beating and maintenance of mucus hydration. The underlying ion transport processes associated with airway surface hydration include epithelial Na+ channel-dependent Na+ absorption occurring in parallel with CFTR and Ca2+-activated Cl− channel-dependent anion secretion, which are coordinately regulated to control the depth of the periciliary liquid layer. Oxidative stress is known to cause both acute and chronic effects on airway ion transport function, and an increasing number of studies in the past few years have identified an important role for autophagy as part of the physiological response to the damaging effects of oxidation. In this review, recent studies addressing the influence of oxidative stress and autophagy on airway ion transport pathways, along with results showing the potential of autophagy modulators in restoring the function of ion channels involved in transepithelial electrolyte transport necessary for effective mucociliary clearance, are presented.

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Autophagy-regulating protease Atg4: structure, function, regulation and inhibition

Cited by 132 publications

References 71 publications

Biological functions of the autophagy-related proteins Atg4 and Atg8 in Cryptococcus neoformans

Biological functions of the autophagy-related proteins Atg4 and Atg8 in Cryptococcus neoformans

Linking Autophagy to Abiotic and Biotic Stress Responses

Oxidative stress, autophagy and airway ion transport

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