WIPI β-propellers in autophagy-related diseases and longevity

2013 ◽  
Vol 41 (4) ◽  
pp. 962-967 ◽  
Author(s):  
Daniela Bakula ◽  
Zsuzsanna Takacs ◽  
Tassula Proikas-Cezanne
Keyword(s):  
Essential Role ◽  
Mammalian Target Of Rapamycin ◽  
Membrane Vesicles ◽  
Catabolic Pathway ◽  
Autophagosome Formation ◽  
Cytoplasmic Material ◽  
Evolutionarily Conserved ◽  
Initiation Step ◽  
Conserved Amino Acids

Autophagy is a catabolic pathway in which the cell sequesters cytoplasmic material, including long-lived proteins, lipids and organelles, in specialized double-membrane vesicles, called autophagosomes. Subsequently, autophagosomes communicate with the lysosomal compartment and acquire acidic hydrolases for final cargo degradation. This process of partial self-eating secures the survival of eukaryotic cells during starvation periods and is critically regulated by mTORC1 (mammalian target of rapamycin complex 1). Under nutrient-poor conditions, inhibited mTORC1 permits localized PtdIns(3)P production at particular membranes that contribute to autophagosome formation. Members of the human WIPI (WD-repeat protein interacting with phosphoinositides) family fulfil an essential role as PtdIns(3)P effectors at the initiation step of autophagosome formation. In the present article, we discuss the role of human WIPIs in autophagy, and the identification of evolutionarily conserved amino acids of WIPI-1 that confer PtdIns(3)P binding downstream of mTORC1 inhibition. We also discuss the PtdIns(3)P effector function of WIPIs in the context of longevity and autophagy-related human diseases, such as cancer and neurodegeneration.

scholarly journals The Atg8 Conjugation System Is Indispensable for Proper Development of Autophagic Isolation Membranes in Mice

2008 ◽  
Vol 19 (11) ◽  
pp. 4762-4775 ◽  
Author(s):  
Yu-shin Sou ◽  
Satoshi Waguri ◽  
Jun-ichi Iwata ◽  
Takashi Ueno ◽  
Tsutomu Fujimura ◽  
...  
Keyword(s):  
Essential Role ◽  
Degradation Pathway ◽  
Conjugation System ◽  
Autophagosome Formation ◽  
Gene Encoding ◽  
Genetic Studies ◽  
Evolutionarily Conserved ◽  
Deficient Mice ◽  
Mouse Genetic

Autophagy is an evolutionarily conserved bulk-protein degradation pathway in which isolation membranes engulf the cytoplasmic constituents, and the resulting autophagosomes transport them to lysosomes. Two ubiquitin-like conjugation systems, termed Atg12 and Atg8 systems, are essential for autophagosomal formation. In addition to the pathophysiological roles of autophagy in mammals, recent mouse genetic studies have shown that the Atg8 system is predominantly under the control of the Atg12 system. To clarify the roles of the Atg8 system in mammalian autophagosome formation, we generated mice deficient in Atg3 gene encoding specific E2 enzyme for Atg8. Atg3-deficient mice were born but died within 1 d after birth. Conjugate formation of mammalian Atg8 homologues was completely defective in the mutant mice. Intriguingly, Atg12–Atg5 conjugation was markedly decreased in Atg3-deficient mice, and its dissociation from isolation membranes was significantly delayed. Furthermore, loss of Atg3 was associated with defective process of autophagosome formation, including the elongation and complete closure of the isolation membranes, resulting in malformation of the autophagosomes. The results indicate the essential role of the Atg8 system in the proper development of autophagic isolation membranes in mice.

Essential Role of Mammalian Target of Rapamycin (mTOR) in LH-dependent Testosterone Production in Rat Leydig Cells.

2010 ◽  
Vol 83 (Suppl_1) ◽  
pp. 420-420 ◽  
Author(s):  
Ana Cecilia M. Millena ◽  
Xiaoying Hou ◽  
John S. Davis ◽  
Shafiq A. Khan
Keyword(s):  
Leydig Cells ◽  
Essential Role ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Testosterone Production

scholarly journals Selective Autophagy inDrosophila

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Ioannis P. Nezis
Keyword(s):  
Cellular Response ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Model Organism ◽  
Major Pathway ◽  
Selective Autophagy ◽  
Cytoplasmic Material ◽  
Evolutionarily Conserved ◽  
High Conservation

Autophagy is an evolutionarily conserved process of cellular self-eating and is a major pathway for degradation of cytoplasmic material by the lysosomal machinery. Autophagy functions as a cellular response in nutrient starvation, but it is also associated with the removal of protein aggregates and damaged organelles and therefore plays an important role in the quality control of proteins and organelles. Although it was initially believed that autophagy occurs randomly in the cell, during the last years, there is growing evidence that sequestration and degradation of cytoplasmic material by autophagy can be selective. Given the important role of autophagy and selective autophagy in several disease-related processes such as neurodegeneration, infections, and tumorigenesis, it is important to understand the molecular mechanisms of selective autophagy, especially at the organismal level.Drosophilais an excellent genetically modifiable model organism exhibiting high conservation in the autophagic machinery. However, the regulation and mechanisms of selective autophagy inDrosophilahave been largely unexplored. In this paper, I will present an overview of the current knowledge about selective autophagy inDrosophila.

scholarly journals ATG9 regulates autophagosome progression from the endoplasmic reticulum in Arabidopsis

2017 ◽  
Vol 114 (3) ◽  
pp. E426-E435 ◽  
Author(s):  
Xiaohong Zhuang ◽  
Kin Pan Chung ◽  
Yong Cui ◽  
Weili Lin ◽  
Caiji Gao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Functional Relationship ◽  
Electron Tomography ◽  
Dependent Manner ◽  
Tubular Structures ◽  
Autophagosome Formation ◽  
Cytoplasmic Material ◽  
Dynamic Analyses

Autophagy is a conserved pathway for bulk degradation of cytoplasmic material by a double-membrane structure named the autophagosome. The initiation of autophagosome formation requires the recruitment of autophagy-related protein 9 (ATG9) vesicles to the preautophagosomal structure. However, the functional relationship between ATG9 vesicles and the phagophore is controversial in different systems, and the molecular function of ATG9 remains unknown in plants. Here, we demonstrate that ATG9 is essential for endoplasmic reticulum (ER)-derived autophagosome formation in plants. Through a combination of genetic, in vivo imaging and electron tomography approaches, we show that Arabidopsis ATG9 deficiency leads to a drastic accumulation of autophagosome-related tubular structures in direct membrane continuity with the ER upon autophagic induction. Dynamic analyses demonstrate a transient membrane association between ATG9 vesicles and the autophagosomal membrane during autophagy. Furthermore, trafficking of ATG18a is compromised in atg9 mutants during autophagy by forming extended tubules in a phosphatidylinositol 3-phosphate–dependent manner. Taken together, this study provides evidence for a pivotal role of ATG9 in regulating autophagosome progression from the ER membrane in Arabidopsis.

scholarly journals Formation Process of Autophagosome Is Traced with Apg8/Aut7p in Yeast

1999 ◽  
Vol 147 (2) ◽  
pp. 435-446 ◽  
Author(s):  
Takayoshi Kirisako ◽  
Misuzu Baba ◽  
Naotada Ishihara ◽  
Kouichi Miyazawa ◽  
Mariko Ohsumi ◽  
...  
Keyword(s):  
Formation Process ◽  
Essential Role ◽  
Immunofluorescence Microscopy ◽  
Intracellular Localization ◽  
Null Mutant ◽  
Autophagosome Formation ◽  
Starvation Conditions

We characterized Apg8/Aut7p essential for autophagy in yeast. Apg8p was transcriptionally upregulated in response to starvation and mostly existed as a protein bound to membrane under both growing and starvation conditions. Immunofluorescence microscopy revealed that the intracellular localization of Apg8p changed drastically after shift to starvation. Apg8p resided on unidentified tiny dot structures dispersed in the cytoplasm at growing phase. During starvation, it was localized on large punctate structures, some of which were confirmed to be autophagosomes and autophagic bodies by immuno-EM. Besides these structures, we found that Apg8p was enriched on isolation membranes and in electron less-dense regions, which should contain Apg8p-localized membrane- or lipid-containing structures. These structures would represent intermediate structures during autophagosome formation. Here, we also showed that microtubule does not play an essential role in the autophagy in yeast. The result does not match with the previously proposed role of Apg8/Aut7p, delivery of autophagosome to the vacuole along microtubule. Moreover, it is revealed that autophagosome formation is severely impaired in the apg8 null mutant. Apg8p would play an important role in the autophagosome formation.

scholarly journals Autophagosome Supports Coxsackievirus B3 Replication in Host Cells

2008 ◽  
Vol 82 (18) ◽  
pp. 9143-9153 ◽  
Author(s):  
Jerry Wong ◽  
Jingchun Zhang ◽  
Xiaoning Si ◽  
Guang Gao ◽  
Ivy Mao ◽  
...  
Keyword(s):  
Viral Replication ◽  
Protein Degradation ◽  
Viral Myocarditis ◽  
Membrane Vesicles ◽  
Coxsackievirus B3 ◽  
Host Cells ◽  
Small Interfering Rnas ◽  
Autophagosome Formation ◽  
Cvb3 Infection

ABSTRACT Recent studies suggest a possible takeover of host antimicrobial autophagy machinery by positive-stranded RNA viruses to facilitate their own replication. In the present study, we investigated the role of autophagy in coxsackievirus replication. Coxsackievirus B3 (CVB3), a picornavirus associated with viral myocarditis, causes pronounced intracellular membrane reorganization after infection. We demonstrate that CVB3 infection induces an increased number of double-membrane vesicles, accompanied by an increase of the LC3-II/LC3-I ratio and an accumulation of punctate GFP-LC3-expressing cells, two hallmarks of cellular autophagosome formation. However, protein expression analysis of p62, a marker for autophagy-mediated protein degradation, showed no apparent changes after CVB3 infection. These results suggest that CVB3 infection triggers autophagosome formation without promoting protein degradation by the lysosome. We further examined the role of the autophagosome in CVB3 replication. We demonstrated that inhibition of autophagosome formation by 3-methyladenine or small interfering RNAs targeting the genes critical for autophagosome formation (ATG7, Beclin-1, and VPS34 genes) significantly reduced viral replication. Conversely, induction of autophagy by rapamycin or nutrient deprivation resulted in increased viral replication. Finally, we examined the role of autophagosome-lysosome fusion in viral replication. We showed that blockage of the fusion by gene silencing of the lysosomal protein LAMP2 significantly promoted viral replication. Taken together, our results suggest that the host's autophagy machinery is activated during CVB3 infection to enhance the efficiency of viral replication.

scholarly journals mTOR and Aging: An Old Fashioned Dress

2019 ◽  
Vol 20 (11) ◽  
pp. 2774 ◽  
Author(s):  
Giovanni Stallone ◽  
Barbara Infante ◽  
Concetta Prisciandaro ◽  
Giuseppe Grandaliano
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Nutrient Sensing ◽  
Protective Effects ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Age Related ◽  
Signalling Network ◽  
Evolutionarily Conserved ◽  
Mtor Signalling

Aging is a physiologic/pathologic process characterized by a progressive impairment of cellular functions, supported by the alterations of several molecular pathways, leading to an increased cell susceptibility to injury. This deterioration is the primary risk factor for several major human pathologies. Numerous cellular processes, including genomic instability, telomere erosion, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular signal transduction represent common denominators of aging in different organisms. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the hypothesis that the mTOR signalling network plays a pivotal role in modulating aging. mTOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction, which has been shown to extend lifespan and slow the onset of age-related diseases across species. Herein we discuss the role of mTor signalling network in the development of classic age-related diseases, focused on cardiovascular system, immune response, and cancer.

scholarly journals ER-Targeted Beclin 1 Supports Autophagosome Biogenesis in the Absence of ULK1 and ULK2 Kinases

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 475 ◽  
Author(s):  
Tahira Anwar ◽  
Xiaonan Liu ◽  
Taina Suntio ◽  
Annika Marjamäki ◽  
Joanna Biazik ◽  
...  
Keyword(s):  
Beclin 1 ◽  
Autophagic Flux ◽  
Wild Type ◽  
Autophagosome Formation ◽  
Double Knockout ◽  
Exact Role ◽  
Initiation Phase ◽  
Cytoplasmic Material ◽  
Autophagy Induction

Autophagy transports cytoplasmic material and organelles to lysosomes for degradation and recycling. Beclin 1 forms a complex with several other autophagy proteins and functions in the initiation phase of autophagy, but the exact role of Beclin 1 subcellular localization in autophagy initiation is still unclear. In order to elucidate the role of Beclin 1 localization in autophagosome biogenesis, we generated constructs that target Beclin 1 to the endoplasmic reticulum (ER) or mitochondria. Our results confirmed the proper organelle-specific targeting of the engineered Beclin 1 constructs, and the proper formation of autophagy-regulatory Beclin 1 complexes. The ULK kinases are required for autophagy initiation upstream of Beclin 1, and autophagosome biogenesis is severely impaired in ULK1/ULK2 double knockout cells. We tested whether Beclin 1 targeting facilitated its ability to rescue autophagosome formation in ULK1/ULK2 double knockout cells. ER-targeted Beclin 1 was most effective in the rescue experiments, while mitochondria-targeted and non-targeted Beclin 1 also showed an ability to rescue, but with lower activity. However, none of the constructs was able to increase autophagic flux in the knockout cells. We also showed that wild type Beclin 1 was enriched on the ER during autophagy induction, and that ULK1/ULK2 facilitated the ER-enrichment of Beclin 1 under basal conditions. The results suggest that one of the functions of ULK kinases may be to enhance Beclin 1 recruitment to the ER to drive autophagosome formation.

scholarly journals Autophagy plays a double-edged sword role in liver diseases

2021 ◽  
Author(s):  
Jing-chao Zhou ◽  
Jing-lin Wang ◽  
Hao-zhen Ren ◽  
Xiao-lei Shi
Keyword(s):  
Liver Diseases ◽  
Alcoholic Hepatitis ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Building Blocks ◽  
Cell Types ◽  
Evolutionarily Conserved ◽  
Constitutive Process ◽  
New Strategies

Abstract As a highly evolutionarily conserved process, autophagy can be found in all types of eukaryotic cells. Such a constitutive process maintains cellular homeostasis in a wide variety of cell types through the encapsulation of damaged proteins or organelles into double-membrane vesicles. Autophagy not only simply eliminates materials but also serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Previous studies have primarily recognized the role of autophagy in the degradation of dysfunctional proteins and unwanted organelles. However, there are findings of autophagy in physiological and pathological processes. In hepatocytes, autophagy is not only essential for homeostatic functions but also implicated in some diseases, such as viral hepatitis, alcoholic hepatitis, and hepatic failure. In the present review, we summarized the molecular mechanisms of autophagy and its role in several liver diseases and put forward several new strategies for the treatment of liver disease.

scholarly journals Atg8a interacts with transcription factor Sequoia to control the expression of autophagy genes in Drosophila

2019 ◽  
Author(s):  
Anne-Claire Jacomin ◽  
Stavroula Petridi ◽  
Marisa DiMonaco ◽  
Ashish Jain ◽  
Zambarlal Bhujabal ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dependent Manner ◽  
Autophagosome Formation ◽  
Regulation Of Expression ◽  
Cytoplasmic Material ◽  
Evolutionarily Conserved ◽  
Enhanced Expression ◽  
Related Proteins ◽  
Lir Motif ◽  
Nuclear Acetyltransferase

SUMMARYAutophagy is a fundamental, evolutionarily conserved, process in which cytoplasmic material is degraded through the lysosomal pathway [1–7]. One of the most important and well-studied autophagy-related proteins is LC3 [Microtubule-associated protein 1 light chain 3, (called Atg8 in yeast and Drosophila)], which participates in autophagosome formation and autophagy cargo selection in the cytoplasm, and is one of the most widely utilized markers of autophagy [8, 9]. Despite growing evidence that LC3 is enriched in the nucleus, little is known about the mechanisms involved in targeting LC3 to the nucleus and the nuclear components it interacts with [10–13]. Here we show that Drosophila Atg8a protein, homologous to mammalian LC3 and yeast Atg8, interacts with the transcription factor Sequoia in a LIR-motif dependent manner. We show that Sequoia depletion induces autophagy in nutrient rich conditions through enhanced expression of autophagy genes. We also show that Atg8a interacts with YL-1, a component of a nuclear acetyltransferase complex, and is acetylated at position K46. Additionally, we show that Atg8a interacts with the deacetylase Sir2, which deacetylates Atg8a during starvation in order to activate autophagy. Our results suggest a mechanism of regulation of expression of autophagy genes by Atg8a, which is linked to its acetylation status and its interaction with Sequoia, YL-1 and Sir2.

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