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Macroautophagy is characterized by the de novo formation of double-membrane vesicles termed autophagosomes. The precursor structure of autophagosomes is a membrane cistern called phagophore, which elongates through a massive acquisition of lipids until closure. The phagophore establishes membrane-contact sites (MCSs) with the endoplasmic reticulum (ER), where conserved ATG proteins belonging to the ATG9 lipid scramblase, ATG2 lipid transfer and Atg18/WIPI4 ß-propeller families concentrate. Several recent in vivo and in vitro studies have uncovered the relevance of these proteins and MCSs in the lipid supply required for autophagosome formation. Although important conceptual advances have been reached, the functional interrelationship between ATG9, ATG2 and Atg18/WIPI4 proteins at the phagophore-ER MCSs and their role in the phagophore expansion are not completely understood. In this review, we describe the current knowledge about the structure, interactions, localizations, and molecular functions of these proteins, with a particular emphasis on the yeast Saccharomyces cerevisiae and mammalian systems.
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Autophagy is well-known as an internal catabolic process that is evolutionarily conserved and performs the key biological function in maintaining cellular homeostasis. It is tightly controlled by several autophagy-related (ATG) proteins, which are closely associated with many types of human cancers. However, what has remained controversial is the janus roles of autophagy in cancer progression. Interestingly, the biological function of long non-coding RNAs (lncRNAs) in autophagy has been gradually understood in different types of human cancers. More recently, numerous studies have demonstrated that several lncRNAs may regulate some ATG proteins and autophagy-related signaling pathways to either activate or inhibit the autophagic process in cancer. Thus, in this review, we summarize the latest advance in the knowledge of the complicated relationships between lncRNAs and autophagy in cancer. Also, the in-depth dissection of the lncRNAs-autophagy-cancers axis involved in this review would shed new light on discovery of more potential cancer biomarkers and therapeutic targets in the future.
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Neoplasias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/metabolismo , Autofagia , Homeostase , Transdução de SinaisRESUMO
Autophagy is an evolutionarily well-conserved cellular catabolic pathway in eukaryotic cells and plays an important role in cellular processes. Autophagy is regulated by autophagy-associated (ATG) proteins. Among these ATG proteins, the ubiquitin-like protein ATG8/LC3 is essential for autophagosome formation and function. In this study, the potato StATG8 family showed clade I and clade II with significantly different sequences. Expression of the StATG8 family was also increased in senescence. Interestingly, the expression of the StATG8 and other core StATG genes decreased in potato tubers as the tubers matured. The StATG8 family also responded to a variety of stresses such as heat, wounding, salicylic acid, and salt stress. We also found that some Arabidopsis WRKY transcription factors interacted with the StATG8 protein in planta. Based on group II-a WRKY, StATG8-WRKY interaction is independent of the ATG8 interacting motif (AIM) or LC3 interacting region (LIR) motif. This study showed that the StATG8 family had diverse functions in tuber maturation and multiple stress responses in potatoes. Additionally, StATG8 may have an unrelated autophagy function in the nucleus with the WRKY transcription factor.
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Macroautophagy/autophagy is a conserved catabolic pathway during which cellular material is sequestered within newly formed double-membrane vesicles called autophagosomes and delivered to the lytic compartment of eukaryotic cells for degradation. Autophagosome biogenesis depends on the core autophagy-related (Atg) machinery, and involves a massive supply and remodelling of membranes. To gain insight into the lipid remodelling mechanisms during autophagy, we have systematically investigated whether lipid flippases are required for this pathway in the yeast Saccharomyces cerevisiae. We found that the flippase Drs2, which transfers phosphatidylserine and phosphatidylethanolamine from the lumenal to the cytosolic leaflet of the limiting membrane at the trans-Golgi network, is required for normal progression of autophagy. We also show that Drs2 is important for the trafficking of the core Atg protein Atg9. Atg9 is a transmembrane protein important for autophagosome biogenesis and its anterograde transport from its post-Golgi reservoirs to the site of autophagosome formation is severely impaired in the absence of Drs2. Thus, our results identify a novel autophagy player and highlight that membrane asymmetry regulates early autophagy steps.
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Autophagy is an evolutionarily conserved signaling pathway to deliver dysfunctional proteins or organelles into lysosomes for degradation and recycling, which is an important pathway for normal homeostasis. Autophagy dysfunction can lead to various diseases, particularly cancer. Autophagy not only plays a role in tumor suppression, but it also serves as a tumor promoter in cancer malignancy. In this review, we summarize the involvement of autophagy-related (ATG) proteins in autophagy signaling and the role of autophagy in cancer progression. The effectiveness of US Food and Drug Administration-approved drugs in regulating autophagic flux and suppressing cancer cells is also discussed. Moreover, since clinically available drugs do not specifically target ATG proteins, there is little doubt that their cancer suppression function is autophagy dependent. Therefore, this review also discusses several inhibitors against ATG proteins, such as ULK1/2, ATG4, and VPS34 to suppress cancer cells. Autophagy modulators can be either used alone or combined with chemotherapy or radiation therapy to enhance the efficacy of current treatments for certain types of cancer. This review summarizes current autophagy modulation used as a potential strategy for targeted cancer therapy.
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Autofagia , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Humanos , Transdução de SinaisRESUMO
Autophagy, originally described as a conserved bulk degradation pathway important to maintain cellular homeostasis during starvation, has also been implicated in playing a central role in multiple physiological processes. For example, autophagy is part of our innate immunity by targeting intracellular pathogens to lysosomes for degradation in a process called xenophagy. Coevolution and adaptation between viruses and autophagy have armed viruses with a multitude of strategies to counteract the antiviral functions of the autophagy pathway. In addition, some viruses have acquired mechanisms to exploit specific functions of either autophagy or the key components of this process, the autophagy-related (ATG) proteins, to promote viral replication and pathogenesis. In this chapter, we describe several examples where the strategy employed by a virus to subvert autophagy has been described with molecular detail. Their stratagems positively or negatively target practically all the steps of autophagy, including the signaling pathways regulating this process. This highlights the intricate relationship between autophagy and viruses and how by commandeering autophagy, viruses have devised ways to fine-tune their replication.
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Autofagia , Interações Hospedeiro-Patógeno , Viroses/patologia , Fenômenos Fisiológicos Virais , Animais , Apoptose , Autofagossomos/virologia , Autofagia/imunologia , Autofagia/fisiologia , Proteínas Relacionadas à Autofagia/fisiologia , Citocinas/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Endossomos/virologia , Metabolismo Energético/fisiologia , Fator de Iniciação 2 em Eucariotos/fisiologia , Humanos , Evasão da Resposta Imune , Imunidade Inata , Lisossomos/enzimologia , Lisossomos/virologia , Alvo Mecanístico do Complexo 1 de Rapamicina/fisiologia , Fusão de Membrana , Transdução de Sinais , Estresse Fisiológico , Proteínas Virais/fisiologia , Viroses/imunologia , Replicação ViralRESUMO
In autophagy, Atg proteins organize the pre-autophagosomal structure (PAS) to initiate autophagosome formation. Previous studies in yeast revealed that the autophagy-related E3 complex Atg12-Atg5-Atg16 is recruited to the PAS via Atg16 interaction with Atg21, which binds phosphatidylinositol 3-phosphate (PI3P) produced at the PAS, to stimulate conjugation of the ubiquitin-like protein Atg8 to phosphatidylethanolamine. Here, we discover a novel mechanism for the PAS targeting of Atg12-Atg5-Atg16, which is mediated by the interaction of Atg12 with the Atg1 kinase complex that serves as a scaffold for PAS organization. While autophagy is partially defective without one of these mechanisms, cells lacking both completely lose the PAS localization of Atg12-Atg5-Atg16 and show no autophagic activity. As with the PI3P-dependent mechanism, Atg12-Atg5-Atg16 recruited via the Atg12-dependent mechanism stimulates Atg8 lipidation, but also has the specific function of facilitating PAS scaffold assembly. Thus, this study significantly advances our understanding of the nucleation step in autophagosome formation.
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Autofagossomos/metabolismo , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína 5 Relacionada à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Autofagossomos/enzimologia , Autofagia , Endopeptidases/metabolismo , Deleção de Genes , Ligação Proteica , Proteínas Quinases/metabolismo , Transporte Proteico , Saccharomyces cerevisiae/enzimologiaRESUMO
Autophagy is an intracellular degradation system conserved among eukaryotes that mediates the degradation of various biomolecules and organelles. During autophagy, a double membrane-bound organelle termed an autophagosome is synthesized de novo and delivers targets from the cytoplasm to the lysosomes for degradation. Autophagosome formation involves complex and dynamic membrane rearrangements, which are regulated by dozens of autophagy-related (Atg) proteins. In this review, we summarize our current knowledge of membrane-binding domains and motifs in Atg proteins and discuss their roles in autophagy.
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Proteínas Relacionadas à Autofagia/química , Autofagia , Membrana Celular/química , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Sítios de Ligação , Membrana Celular/metabolismo , Eucariotos/química , Eucariotos/metabolismo , Humanos , Lisossomos/química , Lisossomos/metabolismo , Organelas/química , Organelas/metabolismoRESUMO
Autophagy is one of the most elaborative membrane remodeling systems in eukaryotic cells. Its major function is to recycle cytoplasmic material by delivering it to lysosomes for degradation. To achieve this, a membrane cisterna is formed that gradually captures cargo such as organelles or protein aggregates. The diversity of cargo requires autophagy to be highly versatile to adapt the shape of the phagophore to its substrate. Upon closure of the phagophore, a double-membrane-surrounded autophagosome is formed that eventually fuses with lysosomes. In response to environmental cues such as cytotoxicity or starvation, bulk cytoplasm can be captured and delivered to lysosomes. Autophagy thus supports cellular survival under adverse conditions. During the past decades, groundbreaking genetic and cell biological studies have identified the core machinery involved in the process. In this Review, we are focusing on in vitro reconstitution approaches to decipher the details and spatiotemporal control of autophagy, and how such studies contributed to our current understanding of the pathways in yeast and mammals. We highlight studies that revealed the function of the autophagy machinery at a molecular level with respect to its capacity to remodel membranes.
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Autofagossomos/metabolismo , Autofagia/fisiologia , Lisossomos/metabolismo , Fagossomos/metabolismo , Animais , Humanos , Membranas/metabolismo , Proteínas/metabolismoRESUMO
The biogenesis of double-membrane vesicles called autophagosomes, which sequester and transport intracellular material for degradation in lysosomes or vacuoles, is a central event in autophagy. This process requires a unique set of factors called autophagy-related (Atg) proteins. The Atg proteins assemble to organize the preautophagosomal structure (PAS), at which a cup-shaped membrane, the isolation membrane (or phagophore), forms and expands to become the autophagosome. The molecular mechanism of autophagosome biogenesis remains poorly understood. Previous studies have shown that Atg2 forms a complex with the phosphatidylinositol 3-phosphate (PI3P)-binding protein Atg18 and localizes to the PAS to initiate autophagosome biogenesis; however, the molecular function of Atg2 remains unknown. In this study, we show that Atg2 has two membrane-binding domains in the N- and C-terminal regions and acts as a membrane tether during autophagosome formation in the budding yeast Saccharomyces cerevisiae An amphipathic helix in the C-terminal region binds to membranes and facilitates Atg18 binding to PI3P to target the Atg2-Atg18 complex to the PAS. The N-terminal region of Atg2 is also involved in the membrane binding of this protein but is dispensable for the PAS targeting of the Atg2-Atg18 complex. Our data suggest that this region associates with the endoplasmic reticulum (ER) and is responsible for the formation of the isolation membrane at the PAS. Based on these results, we propose that the Atg2-Atg18 complex tethers the PAS to the ER to initiate membrane expansion during autophagosome formation.
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Autofagossomos/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Autofagossomos/química , Proteínas Relacionadas à Autofagia/genética , Membranas Intracelulares/metabolismo , Proteínas de Membrana/genética , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Domínios Proteicos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genéticaRESUMO
Macroautophagy, or simply autophagy, is a degradative pathway that delivers cytoplasmic components, including cytosol and organelles, to the lysosome in double-membrane vesicles called autophagosomes. This process is initiated at the pre-autophagosomal structure or phagophore assembly site and involves a number of highly conserved autophagy-related proteins. These support the generation and conversion of an open membranous cistern known as the phagophore or isolation membrane into a closed autophagosome. Within this review, we will focus on recent insights into the molecular events following the sealing/completion of an autophagosome, which lead to its maturation and subsequent fusion with endosomes/lysosomes.
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Autofagossomos/fisiologia , Autofagia , Endossomos/fisiologia , Lisossomos/fisiologia , Animais , Citosol/metabolismo , Humanos , Mamíferos/metabolismo , Proteínas SNARE/metabolismo , Leveduras/metabolismoRESUMO
Autophagy (literally 'self-eating') is an evolutionarily conserved degradation process where cytoplasmic components are engulfed by vesicles called autophagosomes, which are then delivered to lysosomes, where their contents are degraded. Under stress conditions, such as starvation or oxidative stress, autophagy is upregulated in order to degrade macromolecules and restore the nutrient balance. The source of membranes that participate in the initial formation of phagophores is still incompletely understood and many intracellular structures have been shown to act as lipid donors, including the endoplasmic reticulum, Golgi, nucleus, mitochondria and the plasma membrane. Here, we focus on the contributions of the plasma membrane to autophagosome biogenesis governed by ATG16L1 and ATG9A trafficking, and summarize the physiological and pathological implications of this macroautophagy route, from development and stem cell fate to neurodegeneration and cancer.
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Proteínas Relacionadas à Autofagia/genética , Autofagia/genética , Membrana Celular/genética , Proteínas de Membrana/genética , Proteínas de Transporte Vesicular/genética , Animais , Autofagossomos/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Membrana Celular/metabolismo , Endocitose/genética , Humanos , Lisossomos/genética , Lisossomos/metabolismo , Mamíferos , Proteínas de Membrana/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Estresse Oxidativo/genética , Transporte Proteico/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
Recent studies have unveiled the vital role of autophagy in organelle degradation. Our new study in yeast revealed that autophagy targets the endoplasmic reticulum, and even the nucleus, under starvation conditions. Two landmark proteins that direct these organelles to autophagic degradation have been identified, allowing us to dissect the molecular mechanisms and physiological roles of these new pathways.
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ULK1 and ATG13 assemble with RB1CC1/FIP200 and ATG101 to form a macroautophagy (hereafter autophagy) induction (ULK1) complex in higher eukaryotes. The yeast counterpart, the Atg1 complex, is comprised of Atg1 and Atg13 (ULK1 and ATG13 homologs), Atg17 (a proposed functional homolog of RB1CC1), and either the Atg101 subunit (in Schizosaccharomyces pombe) or the Atg29-Atg31 heterodimer (in Saccharomyces cerevisiae). With mutual exclusivity of, and no detectable homology between, the Atg29-Atg31 dimer and Atg101, knowledge about the roles of these proteins in autophagy induction is an important piece in the puzzle of understanding the molecular mechanism of autophagy initiation. A recent study reporting the structure of the S. pombe homolog Atg101 bound to the Atg13HORMA domain is a notable contribution to this knowledge (see the punctum in this issue of the journal).
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Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes - including oxidative stress, quality control mechanisms and apoptotic signaling - on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.