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Open AccessEditorial

Special Issue on “Proteostasis and Autophagy”

by Andreas Kern and Christian Behl

Cells 2019, 8(7), 642; https://doi.org/10.3390/cells8070642 - 26 Jun 2019

Cited by 3 | Viewed by 3568

Abstract

Autophagy is a highly conserved eukaryotic pathway responsible for the lysosomal degradation (and subsequent recycling) of cellular components such as proteins, protein aggregates, and a growing number of organelles or cellular compartments [...] Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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Research

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21 pages, 4099 KiB

Open AccessFeature PaperArticle

ATG-18 and EPG-6 are Both Required for Autophagy but Differentially Contribute to Lifespan Control in Caenorhabditis elegans

by Zsuzsanna Takacs, Katharina Sporbeck, Jennifer Stoeckle, Maria Jhaneth Prado Carvajal, Mona Grimmel and Tassula Proikas-Cezanne

Cells 2019, 8(3), 236; https://doi.org/10.3390/cells8030236 - 12 Mar 2019

Cited by 4 | Viewed by 5642

Abstract

During macroautophagy, the human WIPI (WD-repeat protein interacting with phosphoinositides) proteins (WIPI1–4) function as phosphatidylinositol 3-phosphate effectors at the nascent autophagosome. Likewise, the two WIPI homologues in Caenorhabditis elegans, ATG-18 and EPG-6, play important roles in autophagy, whereby ATG-18 is considered to [...] Read more.

During macroautophagy, the human WIPI (WD-repeat protein interacting with phosphoinositides) proteins (WIPI1–4) function as phosphatidylinositol 3-phosphate effectors at the nascent autophagosome. Likewise, the two WIPI homologues in Caenorhabditis elegans, ATG-18 and EPG-6, play important roles in autophagy, whereby ATG-18 is considered to act upstream of EPG-6 at the onset of autophagy. Due to its essential role in autophagy, ATG-18 was found to be also essential for lifespan extension in Caenorhabditis elegans; however, this has not yet been addressed with regard to EPG-6. Here, we wished to address this point and generated mutant strains that expressed the autophagy marker GFP::LGG-1 (GFP-LC3 in mammals) and harbored functional deletions of either atg-18 (atg18(gk378)), epg-6 (epg-6(bp242)) or both (atg-18(gk378);epg-6(bp242)). Using quantitative fluorescence microscopy, Western blotting, and lifespan assessments, we provide evidence that in the absence of either ATG-18 or EPG-6 autophagy was impaired, and while atg-18 mutant animals showed a short-lived phenotype, lifespan was significantly increased in epg-6 mutant animals. We speculate that the long-lived phenotype of epg-6 mutant animals points towards an autophagy-independent function of EPG-6 in lifespan control that warrants further mechanistic investigations in future studies. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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13 pages, 2513 KiB

Open AccessEditor’s ChoiceArticle

Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo

by Maximilian G. Christ, Heike Huesmann, Heike Nagel, Andreas Kern and Christian Behl

Cells 2019, 8(3), 211; https://doi.org/10.3390/cells8030211 - 2 Mar 2019

Cited by 52 | Viewed by 12502

Abstract

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and [...] Read more.

Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer’s disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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14 pages, 3147 KiB

Open AccessArticle

Control of the Epithelial-to-Mesenchymal Transition and Cancer Metastasis by Autophagy-Dependent SNAI1 Degradation

by Sahib Zada, Jin Seok Hwang, Mahmoud Ahmed, Trang Huyen Lai, Trang Minh Pham and Deok Ryong Kim

Cells 2019, 8(2), 129; https://doi.org/10.3390/cells8020129 - 6 Feb 2019

Cited by 40 | Viewed by 5567

Abstract

Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against [...] Read more.

Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against genotoxic components, leading to cancerous transformation. It can also promote cancer cell survival by supplying minimal amounts of nutrients during cancer progression. However, the molecular mechanisms underlying how autophagy regulates the epithelial-to-mesenchymal transition (EMT) and cancer metastasis are unknown. Here, we show that starvation-induced autophagy promotes Snail (SNAI1) degradation and inhibits EMT and metastasis in cancer cells. Interestingly, SNAI1 proteins were physically associated and colocalized with LC3 and SQSTM1 in cancer cells. We also found a significant decrease in the levels of EMT and metastatic proteins under starvation conditions. Furthermore, ATG7 knockdown inhibited autophagy-induced SNAI1 degradation in the cytoplasm, which was associated with a decrease in SNAI1 nuclear translocation. Moreover, cancer cell invasion and migration were significantly inhibited by starvation-induced autophagy. These findings suggest that autophagy-dependent SNAI1 degradation could specifically regulate EMT and cancer metastasis during tumorigenesis. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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27 pages, 7912 KiB

Open AccessArticle

Functional Characterization of Ubiquitin-Like Core Autophagy Protein ATG12 in Dictyostelium discoideum

by Sarah Fischer, Ramesh Rijal, Peter Frommolt, Prerana Wagle, Roman Konertz, Jan Faix, Susanne Meßling and Ludwig Eichinger

Cells 2019, 8(1), 72; https://doi.org/10.3390/cells8010072 - 19 Jan 2019

Cited by 19 | Viewed by 6219

Abstract

Autophagy is a highly conserved intracellular degradative pathway that is crucial for cellular homeostasis. During autophagy, the core autophagy protein ATG12 plays, together with ATG5 and ATG16, an essential role in the expansion of the autophagosomal membrane. In this study we analyzed gene [...] Read more.

Autophagy is a highly conserved intracellular degradative pathway that is crucial for cellular homeostasis. During autophagy, the core autophagy protein ATG12 plays, together with ATG5 and ATG16, an essential role in the expansion of the autophagosomal membrane. In this study we analyzed gene replacement mutants of atg12 in Dictyostelium discoideum AX2 wild-type and ATG16‾ cells. RNA_seq analysis revealed a strong enrichment of, firstly, autophagy genes among the up-regulated genes and, secondly, genes implicated in cell motility and phagocytosis among the down-regulated genes in the generated ATG12‾, ATG16‾ and ATG12‾/16‾ cells. The mutant strains showed similar defects in fruiting body formation, autolysosome maturation, and cellular viability, implying that ATG12 and ATG16 act as a functional unit in canonical autophagy. In contrast, ablation of ATG16 or of ATG12 and ATG16 resulted in slightly more severe defects in axenic growth, macropinocytosis, and protein homeostasis than ablation of only ATG12, suggesting that ATG16 fulfils an additional function in these processes. Phagocytosis of yeast, spore viability, and maximal cell density were much more affected in ATG12‾/16‾ cells, indicating that both proteins also have cellular functions independent of each other. In summary, we show that ATG12 and ATG16 fulfil autophagy-independent functions in addition to their role in canonical autophagy. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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8 pages, 1832 KiB

Open AccessCommunication

Possible Mechanisms by which Stefin B could Regulate Proteostasis and Oxidative Stress

by Eva Žerovnik

Cells 2019, 8(1), 70; https://doi.org/10.3390/cells8010070 - 18 Jan 2019

Cited by 4 | Viewed by 4432

Abstract

Human stefin B is a protease inhibitor from the family of cystatins. It was reported that it forms oligomers in cells. We have shown that it has a role in cell’s response to misfolded proteins. We also have shown that its oligomers bind [...] Read more.

Human stefin B is a protease inhibitor from the family of cystatins. It was reported that it forms oligomers in cells. We have shown that it has a role in cell’s response to misfolded proteins. We also have shown that its oligomers bind amyloid-beta (Aβ). Here, we discuss ways, how stefin B could reduce build-up of protein aggregates by other proteins and consequently reduces ROS and, how this might be connected to autophagy. When overexpressed, stefin B forms protein aggregates itself and these protein aggregates induce autophagy. Similarly, cystatin C was shown to bind Aβ and to induce autophagy. It is also suggested how more knowledge about the role of stefin B in a cell’s response to misfolded proteins could be used to modulate progressive myoclonus epilepsy of type 1 EPM1 disease. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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Review

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21 pages, 2038 KiB

Open AccessReview

Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer’s Disease

by P. Hemachandra Reddy and Darryll MA Oliver

Cells 2019, 8(5), 488; https://doi.org/10.3390/cells8050488 - 22 May 2019

Cited by 351 | Viewed by 21739

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intense research have revealed that multiple cellular changes are implicated in the development and progression of AD, including mitochondrial damage, synaptic dysfunction, amyloid beta [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intense research have revealed that multiple cellular changes are implicated in the development and progression of AD, including mitochondrial damage, synaptic dysfunction, amyloid beta (Aβ) formation and accumulation, hyperphosphorylated tau (P-Tau) formation and accumulation, deregulated microRNAs, synaptic damage, and neuronal loss in patients with AD. Among these, mitochondrial dysfunction and synaptic damage are early events in the disease process. Recent research also revealed that Aβ and P-Tau-induced defective autophagy and mitophagy are prominent events in AD pathogenesis. Age-dependent increased levels of Aβ and P-Tau reduced levels of several autophagy and mitophagy proteins. In addition, abnormal interactions between (1) Aβ and mitochondrial fission protein Drp1; (2) P-Tau and Drp1; and (3) Aβ and PINK1/parkin lead to an inability to clear damaged mitochondria and other cellular debris from neurons. These events occur selectively in affected AD neurons. The purpose of our article is to highlight recent developments of a Aβ and P-Tau-induced defective autophagy and mitophagy in AD. This article also summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics (increased fission and reduced fusion), defective mitochondrial biogenesis, reduced ATP, increased free radicals and lipid peroxidation, and decreased cytochrome c oxidase (COX) activity and calcium dyshomeostasis in AD pathogenesis. Our article also discusses how reduced levels of Drp1, Aβ, and P-Tau can enhance the clearance of damaged mitochondria and other cellular debris by autophagy and mitophagy mechanisms. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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15 pages, 1524 KiB

Open AccessReview

The Role of Primary Cilia in the Crosstalk between the Ubiquitin–Proteasome System and Autophagy

by Antonia Wiegering, Ulrich Rüther and Christoph Gerhardt

Cells 2019, 8(3), 241; https://doi.org/10.3390/cells8030241 - 14 Mar 2019

Cited by 20 | Viewed by 6717

Abstract

Protein degradation is a pivotal process for eukaryotic development and homeostasis. The majority of proteins are degraded by the ubiquitin–proteasome system and by autophagy. Recent studies describe a crosstalk between these two main eukaryotic degradation systems which allows for establishing a kind of [...] Read more.

Protein degradation is a pivotal process for eukaryotic development and homeostasis. The majority of proteins are degraded by the ubiquitin–proteasome system and by autophagy. Recent studies describe a crosstalk between these two main eukaryotic degradation systems which allows for establishing a kind of safety mechanism. If one of these degradation systems is hampered, the other compensates for this defect. The mechanism behind this crosstalk is poorly understood. Novel studies suggest that primary cilia, little cellular protrusions, are involved in the regulation of the crosstalk between the two degradation systems. In this review article, we summarise the current knowledge about the association between cilia, the ubiquitin–proteasome system and autophagy. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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16 pages, 953 KiB

Open AccessFeature PaperReview

Presenilins and γ-Secretase in Membrane Proteostasis

by Naoto Oikawa and Jochen Walter

Cells 2019, 8(3), 209; https://doi.org/10.3390/cells8030209 - 1 Mar 2019

Cited by 51 | Viewed by 8911

Abstract

The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein (APP) and the generation of amyloid β-protein (Aβ). The two homologous proteins PS1 and PS2 represent the catalytic subunits [...] Read more.

The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein (APP) and the generation of amyloid β-protein (Aβ). The two homologous proteins PS1 and PS2 represent the catalytic subunits of distinct γ-secretase complexes that mediate a variety of cellular processes, including membrane protein metabolism, signal transduction, and cell differentiation. While the intramembrane cleavage of select proteins by γ-secretase is critical in the regulation of intracellular signaling pathways, the plethora of identified protein substrates could also indicate an important role of these enzyme complexes in membrane protein homeostasis. In line with this notion, PS proteins and/or γ-secretase has also been implicated in autophagy, a fundamental process for the maintenance of cellular functions and homeostasis. Dysfunction in the clearance of proteins in the lysosome and during autophagy has been shown to contribute to neurodegeneration. This review summarizes the recent knowledge about the role of PS proteins and γ-secretase in membrane protein metabolism and trafficking, and the functional relation to lysosomal activity and autophagy. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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18 pages, 268 KiB

Open AccessFeature PaperReview

Is Autophagy Involved in the Diverse Effects of Antidepressants?

by Theo Rein

Cells 2019, 8(1), 44; https://doi.org/10.3390/cells8010044 - 12 Jan 2019

Cited by 30 | Viewed by 5298

Abstract

Autophagy has received increased attention as a conserved process governing cellular energy and protein homeostasis that is thus relevant in a range of physiological and pathophysiological conditions. Recently, autophagy has also been linked to depression, mainly through its involvement in the action of [...] Read more.

Autophagy has received increased attention as a conserved process governing cellular energy and protein homeostasis that is thus relevant in a range of physiological and pathophysiological conditions. Recently, autophagy has also been linked to depression, mainly through its involvement in the action of antidepressants. Some antidepressant drugs and psychotropic medication have been reported to exert beneficial effects in other diseases, for example, in cancer and neurodegenerative diseases. This review collates the evidence for the hypothesis that autophagy contributes to the effects of antidepressants beyond depression treatment. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

32 pages, 2091 KiB

Open AccessEditor’s ChoiceReview

The Roles of Ubiquitin-Binding Protein Shuttles in the Degradative Fate of Ubiquitinated Proteins in the Ubiquitin-Proteasome System and Autophagy

by Katarzyna Zientara-Rytter and Suresh Subramani

Cells 2019, 8(1), 40; https://doi.org/10.3390/cells8010040 - 10 Jan 2019

Cited by 92 | Viewed by 14474

Abstract

The ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein quality control (PQC) pathways that are responsible for cellular proteostasis (homeostasis of the proteome) by ensuring the timely degradation of misfolded, damaged, and unwanted proteins. Ubiquitination serves as the degradation signal [...] Read more.

The ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein quality control (PQC) pathways that are responsible for cellular proteostasis (homeostasis of the proteome) by ensuring the timely degradation of misfolded, damaged, and unwanted proteins. Ubiquitination serves as the degradation signal in both these systems, but substrates are precisely targeted to one or the other pathway. Determining how and when cells target specific proteins to these two alternative PQC pathways and control the crosstalk between them are topics of considerable interest. The ubiquitin (Ub) recognition code based on the type of Ub-linked chains on substrate proteins was believed to play a pivotal role in this process, but an increasing body of evidence indicates that the PQC pathway choice is also made based on other criteria. These include the oligomeric state of the Ub-binding protein shuttles, their conformation, protein modifications, and the presence of motifs that interact with ATG8/LC3/GABARAP (autophagy-related protein 8/microtubule-associated protein 1A/1B-light chain 3/GABA type A receptor-associated protein) protein family members. In this review, we summarize the current knowledge regarding the Ub recognition code that is bound by Ub-binding proteasomal and autophagic receptors. We also discuss how cells can modify substrate fate by modulating the structure, conformation, and physical properties of these receptors to affect their shuttling between both degradation pathways. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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13 pages, 629 KiB

Open AccessReview

Emerging Concepts and Functions of Autophagy as a Regulator of Synaptic Components and Plasticity

by YongTian Liang

Cells 2019, 8(1), 34; https://doi.org/10.3390/cells8010034 - 9 Jan 2019

Cited by 45 | Viewed by 8781

Abstract

Protein homeostasis (proteostasis) is crucial to the maintenance of neuronal integrity and function. As the contact sites between neurons, synapses rely heavily on precisely regulated protein-protein interactions to support synaptic transmission and plasticity processes. Autophagy is an effective degradative pathway that can digest [...] Read more.

Protein homeostasis (proteostasis) is crucial to the maintenance of neuronal integrity and function. As the contact sites between neurons, synapses rely heavily on precisely regulated protein-protein interactions to support synaptic transmission and plasticity processes. Autophagy is an effective degradative pathway that can digest cellular components and maintain cellular proteostasis. Perturbations of autophagy have been implicated in aging and neurodegeneration due to a failure to remove damaged proteins and defective organelles. Recent evidence has demonstrated that autophagosome formation is prominent at synaptic terminals and neuronal autophagy is regulated in a compartment-specific fashion. Moreover, synaptic components including synaptic proteins and vesicles, postsynaptic receptors and synaptic mitochondria are known to be degraded by autophagy, thereby contributing to the remodeling of synapses. Indeed, emerging studies indicate that modulation of autophagy may be required for different forms of synaptic plasticity and memory formation. In this review, I will discuss our current understanding of the important role of neuronal/synaptic autophagy in maintaining neuronal function by degrading synaptic components and try to propose a conceptual framework of how the degradation of synaptic components via autophagy might impact synaptic function and contribute to synaptic plasticity. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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20 pages, 1357 KiB

Open AccessReview

The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors

by Zhen Dong and Hongjuan Cui

Cells 2019, 8(1), 4; https://doi.org/10.3390/cells8010004 - 20 Dec 2018

Cited by 33 | Viewed by 7862

Abstract

In normal physiological condition, the maintenance of cellular proteostasis is a prerequisite for cell growth, functioning, adapting to changing micro-environments, and responding to extracellular stress. Cellular proteostasis is maintained by specific proteostasis networks (PNs) to prevent protein misfolding, aggregating, and accumulating in subcellular [...] Read more.

In normal physiological condition, the maintenance of cellular proteostasis is a prerequisite for cell growth, functioning, adapting to changing micro-environments, and responding to extracellular stress. Cellular proteostasis is maintained by specific proteostasis networks (PNs) to prevent protein misfolding, aggregating, and accumulating in subcellular compartments. Commonly, the PNs are composed of protein synthesis, molecular chaperones, endoplasmic reticulum (ER), unfolded protein response (UPR), stress response pathways (SRPs), secretions, ubiquitin proteasome system (UPS), and autophagy-lysosomal pathways (ALPs). Although great efforts have been made to explore the underlying detailed mechanisms of proteostasis, there are many questions remain to explore, especially in proteostasis regulated by the ALPs. Proteostasis out-off-balance is correlated with various human diseases such as diabetes, stroke, inflammation, hypertension, pulmonary fibrosis, and Alzheimer’s disease. Enhanced regulation of PNs is observed in tumors, thereby indicating that proteostasis may play a pivotal role in tumorigenesis and cancer development. Recently, inhibitors targeting the UPS have shown to be failed in solid tumor treatment. However, there is growing evidence showing that the ALPs play important roles in regulation of proteostasis alone or with a crosstalk with other PNs in tumors. In this review, we provide insights into the proteostatic process and how it is regulated by the ALPs, such as macroautophagy, aggrephagy, chaperone-mediated autophagy, microautophagy, as well as mitophagy during tumor development. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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16 pages, 1808 KiB

Open AccessFeature PaperReview

The Role of ATG16 in Autophagy and The Ubiquitin Proteasome System

by Qiuhong Xiong, Wenjing Li, Ping Li, Min Yang, Changxin Wu and Ludwig Eichinger

Cells 2019, 8(1), 2; https://doi.org/10.3390/cells8010002 - 20 Dec 2018

Cited by 47 | Viewed by 9031

Abstract

Autophagy and the ubiquitin proteasome system (UPS) are the two major cellular degradation pathways, which are critical for the maintenance of cell homeostasis. The two pathways differ in their mechanisms and clients. The evolutionary conserved ATG16 plays a key role in autophagy and [...] Read more.

Autophagy and the ubiquitin proteasome system (UPS) are the two major cellular degradation pathways, which are critical for the maintenance of cell homeostasis. The two pathways differ in their mechanisms and clients. The evolutionary conserved ATG16 plays a key role in autophagy and appears to link autophagy with the UPS. Here, we review the role of ATG16 in different species. We summarize the current knowledge of its functions in autophagosome membrane expansion and autophagosome formation, in Crohn’s disease, and in bacterial sequestration. In addition, we provide information on its autophagy-independent functions and its role in the crosstalk between autophagy and the UPS. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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19 pages, 1309 KiB

Open AccessReview

Role of Autophagy in Proteostasis: Friend and Foe in Cardiac Diseases

by Jin Li, Deli Zhang, Marit Wiersma and Bianca J. J. M. Brundel

Cells 2018, 7(12), 279; https://doi.org/10.3390/cells7120279 - 19 Dec 2018

Cited by 43 | Viewed by 6438

Abstract

Due to ageing of the population, the incidence of cardiovascular diseases will increase in the coming years, constituting a substantial burden on health care systems. In particular, atrial fibrillation (AF) is approaching epidemic proportions. It has been identified that the derailment of proteostasis, [...] Read more.

Due to ageing of the population, the incidence of cardiovascular diseases will increase in the coming years, constituting a substantial burden on health care systems. In particular, atrial fibrillation (AF) is approaching epidemic proportions. It has been identified that the derailment of proteostasis, which is characterized by the loss of homeostasis in protein biosynthesis, folding, trafficking, and clearance by protein degradation systems such as autophagy, underlies the development of common cardiac diseases. Among various safeguards within the proteostasis system, autophagy is a vital cellular process that modulates clearance of misfolded and proteotoxic proteins from cardiomyocytes. On the other hand, excessive autophagy may result in derailment of proteostasis and therefore cardiac dysfunction. Here, we review the interplay between autophagy and proteostasis in the healthy heart, discuss the imbalance between autophagy and proteostasis during cardiac diseases, including AF, and finally explore new druggable targets which may limit cardiac disease initiation and progression. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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26 pages, 2178 KiB

Open AccessReview

Autophagy: An Essential Degradation Program for Cellular Homeostasis and Life

by Yoomi Chun and Joungmok Kim

Cells 2018, 7(12), 278; https://doi.org/10.3390/cells7120278 - 19 Dec 2018

Cited by 293 | Viewed by 11796

Abstract

Autophagy is a lysosome-dependent cellular degradation program that responds to a variety of environmental and cellular stresses. It is an evolutionarily well-conserved and essential pathway to maintain cellular homeostasis, therefore, dysfunction of autophagy is closely associated with a wide spectrum of human pathophysiological [...] Read more.

Autophagy is a lysosome-dependent cellular degradation program that responds to a variety of environmental and cellular stresses. It is an evolutionarily well-conserved and essential pathway to maintain cellular homeostasis, therefore, dysfunction of autophagy is closely associated with a wide spectrum of human pathophysiological conditions including cancers and neurodegenerative diseases. The discovery and characterization of the kingdom of autophagy proteins have uncovered the molecular basis of the autophagy process. In addition, recent advances on the various post-translational modifications of autophagy proteins have shed light on the multiple layers of autophagy regulatory mechanisms, and provide novel therapeutic targets for the treatment of the diseases. Full article

(This article belongs to the Special Issue Proteostasis and Autophagy)

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