scholarly journals Key Regulators of Autophagosome Closure

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2814
Author(s):  
Wenyan Jiang ◽  
Xuechai Chen ◽  
Cuicui Ji ◽  
Wenting Zhang ◽  
Jianing Song ◽  
...  
Keyword(s):  
Recent Progress ◽  
Membrane Vesicles ◽  
Rab Gtpase ◽  
The Core ◽  
Escrt Machinery ◽  
Atg Proteins ◽  
Evolutionarily Conserved ◽  
Atg Genes ◽  
Related Proteins ◽  
Key Questions

Autophagy is an evolutionarily conserved pathway, in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes and then transported into lysosomes or vacuoles for degradation. Over 40 conserved autophagy-related (ATG) genes define the core machinery for the five processes of autophagy: initiation, nucleation, elongation, closure, and fusion. In this review, we focus on one of the least well-characterized events in autophagy, namely the closure of the isolation membrane/phagophore to form the sealed autophagosome. This process is tightly regulated by ESCRT machinery, ATG proteins, Rab GTPase and Rab-related proteins, SNAREs, sphingomyelin, and calcium. We summarize recent progress in the regulation of autophagosome closure and discuss the key questions remaining to be addressed.

scholarly journals BPIFB3 Regulates Autophagy and Coxsackievirus B Replication through a Noncanonical Pathway Independent of the Core Initiation Machinery

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Elizabeth Delorme-Axford ◽  
Stefanie Morosky ◽  
Jennifer Bomberger ◽  
Donna B. Stolz ◽  
William T. Jackson ◽  
...  
Keyword(s):  
Membrane Vesicles ◽  
Rna Replication ◽  
Heart Transplants ◽  
The Core ◽  
Coxsackievirus B ◽  
Evolutionarily Conserved ◽  
Novel Host ◽  
Noncanonical Pathway ◽  
Key Steps ◽  
Interfering Rna

ABSTRACTEnteroviruses require autophagy to facilitate the formation of autophagosome (AP)-like double-membrane vesicles that provide the scaffolding for RNA replication. Here, we identify bactericidal/permeability-increasing protein (BPI) fold-containing family B, member 3 (BPIFB3) as a gene whose silencing greatly enhances coxsackievirus B (CVB) replication and induces dramatic alterations in the morphology of CVB-induced replication organelles. We show that BPIFB3 is associated with the endoplasmic reticulum (ER), and its silencing by RNA interference enhances basal levels of autophagy and promotes increased autophagy during CVB replication. Conversely, overexpression of BPIFB3 inhibits CVB replication, dramatically alters the morphology of LC3B-positive vesicles, and suppresses autophagy in response to rapamaycin. In addition, we found that, whereas silencing of core autophagy components associated with the initiation of APs in control cells suppressed CVB replication, silencing of these same components had no effect on CVB-induced autophagy or viral replication in cells transfected with BPIFB3 small interfering RNA. Based on these results, taken together, this study reports on a previously uncharacterized regulator of enterovirus infection that controls replication through a noncanonical pathway independent from the core autophagy initiation machinery.IMPORTANCECoxsackievirus B (CVB) infections are commonly associated with dilated cardiomyopathy, a condition that accounts for nearly half of all heart transplants annually. During infection, CVB co-opts a cellular pathway, termed autophagy, to provide the membranes necessary for its replication. Autophagy is an evolutionarily conserved process by which cells ingest damaged organelles as a means of maintaining cell homeostasis. Here, we report on a novel regulator of autophagy, bactericidal/permeability-increasing protein (BPI) fold-containing family B, member 3 (BPIFB3), whose expression functions to restrict CVB replication by suppressing key steps in the authophagic process. We show that loss of BPIFB3 expression greatly enhances CVB replication while having no effect on replication of poliovirus, a closely related virus. Our results thus identify a novel host cell therapeutic target whose function could be targeted to alter CVB replication.

scholarly journals Piecemeal Microautophagy of the Nucleus Requires the Core Macroautophagy Genes

2008 ◽  
Vol 19 (10) ◽  
pp. 4492-4505 ◽  
Author(s):  
R. Krick ◽  
Y. Muehe ◽  
T. Prick ◽  
S. Bremer ◽  
P. Schlotterhose ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Saccharomyces Cerevisiae ◽  
Fusion Genes ◽  
Vacuole Membrane ◽  
The Core ◽  
Atg Proteins ◽  
Biochemical Assays ◽  
Atg Genes ◽  
Mutant Cells ◽  
Specific Membrane

Autophagy is a diverse family of processes that transport cytoplasm and organelles into the lysosome/vacuole lumen for degradation. During macroautophagy cargo is packaged in autophagosomes that fuse with the lysosome/vacuole. During microautophagy cargo is directly engulfed by the lysosome/vacuole membrane. Piecemeal microautophagy of the nucleus (PMN) occurs in Saccharomyces cerevisiae at nucleus-vacuole (NV) junctions and results in the pinching-off and release into the vacuole of nonessential portions of the nucleus. Previous studies concluded macroautophagy ATG genes are not absolutely required for PMN. Here we report using two biochemical assays that PMN is efficiently inhibited in atg mutant cells: PMN blebs are produced, but vesicles are rarely released into the vacuole lumen. Electron microscopy of arrested PMN structures in atg7, atg8, and atg9 mutant cells suggests that NV-junction–associated micronuclei may normally be released from the nucleus before their complete enclosure by the vacuole membrane. In this regard PMN is similar to the microautophagy of peroxisomes (micropexophagy), where the side of the peroxisome opposite the engulfing vacuole is capped by a structure called the “micropexophagy-specific membrane apparatus” (MIPA). The MIPA contains Atg proteins and facilitates terminal enclosure and fusion steps. PMN does not require the complete vacuole homotypic fusion genes. We conclude that a spectrum of ATG genes is required for the terminal vacuole enclosure and fusion stages of PMN.

scholarly journals Peroxisome Size Provides Insights into the Function of Autophagy-related Proteins

2009 ◽  
Vol 20 (17) ◽  
pp. 3828-3839 ◽  
Author(s):  
Taras Y. Nazarko ◽  
Jean-Claude Farré ◽  
Suresh Subramani
Keyword(s):  
Model System ◽  
Intracellular Bacteria ◽  
Major Pathway ◽  
Selective Autophagy ◽  
Intracellular Degradation ◽  
The Core ◽  
Atg Proteins ◽  
Related Proteins ◽  
Assembly Site ◽  
Yeast Model

Autophagy is a major pathway of intracellular degradation mediated by formation of autophagosomes. Recently, autophagy was implicated in the degradation of intracellular bacteria, whose size often exceeds the capacity of normal autophagosomes. However, the adaptations of the autophagic machinery for sequestration of large cargos were unknown. Here we developed a yeast model system to study the effect of cargo size on the requirement of autophagy-related (Atg) proteins. We controlled the size of peroxisomes before their turnover by pexophagy, the selective autophagy of peroxisomes, and found that peroxisome size determines the requirement of Atg11 and Atg26. Small peroxisomes can be degraded without these proteins. However, Atg26 becomes essential for degradation of medium peroxisomes. Additionally, the pexophagy-specific phagophore assembly site, organized by the dual interaction of Atg30 with functionally active Atg11 and Atg17, becomes essential for degradation of large peroxisomes. In contrast, Atg28 is partially required for all autophagy-related pathways independent of cargo size, suggesting it is a component of the core autophagic machinery. As a rule, the larger the cargo, the more cargo-specific Atg proteins become essential for its sequestration.

scholarly journals Targeting Autophagy to Overcome Human Diseases

2019 ◽  
Vol 20 (3) ◽  
pp. 725 ◽  
Author(s):  
Maria Condello ◽  
Evelin Pellegrini ◽  
Michele Caraglia ◽  
Stefania Meschini
Keyword(s):  
Metabolic Diseases ◽  
Early Stage ◽  
Membrane Vesicles ◽  
Cellular Physiology ◽  
Evolutionarily Conserved ◽  
Cell Components ◽  
Autophagic Process ◽  
Related Proteins

Autophagy is an evolutionarily conserved cellular process, through which damaged organelles and superfluous proteins are degraded, for maintaining the correct cellular balance during stress insult. It involves formation of double-membrane vesicles, named autophagosomes, that capture cytosolic cargo and deliver it to lysosomes, where the breakdown products are recycled back to cytoplasm. On the basis of degraded cell components, some selective types of autophagy can be identified (mitophagy, ribophagy, reticulophagy, lysophagy, pexophagy, lipophagy, and glycophagy). Dysregulation of autophagy can induce various disease manifestations, such as inflammation, aging, metabolic diseases, neurodegenerative disorders and cancer. The understanding of the molecular mechanism that regulates the different phases of the autophagic process and the role in the development of diseases are only in an early stage. There are still questions that must be answered concerning the functions of the autophagy-related proteins. In this review, we describe the principal cellular and molecular autophagic functions, selective types of autophagy and the main in vitro methods to detect the role of autophagy in the cellular physiology. We also summarize the importance of the autophagic behavior in some diseases to provide a novel insight for target therapies.

scholarly journals Structural catalog of core Atg proteins opens new era of autophagy research

2021 ◽  
Author(s):  
Kazuaki Matoba ◽  
Nobuo N Noda
Keyword(s):  
De Novo ◽  
Structural Information ◽  
Membrane Dynamics ◽  
Autophagosome Formation ◽  
New Era ◽  
Intracellular Degradation ◽  
Atg Proteins ◽  
Biological Studies ◽  
Evolutionarily Conserved ◽  
Biological Methods

Summary Autophagy, which is an evolutionarily conserved intracellular degradation system, involves de novo generation of autophagosomes that sequester and deliver diverse cytoplasmic materials to the lysosome for degradation. Autophagosome formation is mediated by approximately 20 core autophagy-related (Atg) proteins, which collaborate to mediate complicated membrane dynamics during autophagy. To elucidate the molecular functions of these Atg proteins in autophagosome formation, many researchers have tried to determine the structures of Atg proteins by using various structural biological methods. Although not sufficient, the basic structural catalog of all core Atg proteins was established. In this review article, we summarize structural biological studies of core Atg proteins, with an emphasis on recently unveiled structures, and describe the mechanistic breakthroughs in autophagy research that have derived from new structural information.

scholarly journals The Landscape of Autophagy-Related (ATG) Genes and Functional Characterization of TaVAMP727 to Autophagy in Wheat

2022 ◽  
Vol 23 (2) ◽  
pp. 891
Author(s):  
Wenjie Yue ◽  
Haobin Zhang ◽  
Xuming Sun ◽  
Ning Su ◽  
Qi Zhao ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Functional Characterization ◽  
Tetraploid Wheat ◽  
Wheat Plant ◽  
Wheat Breeding ◽  
Plant Responses ◽  
Regulation Network ◽  
Atg Genes ◽  
Drought And Salt Stresses ◽  
Related Proteins

Autophagy is an indispensable biological process and plays crucial roles in plant growth and plant responses to both biotic and abiotic stresses. This study systematically identified autophagy-related proteins (ATGs) in wheat and its diploid and tetraploid progenitors and investigated their genomic organization, structure characteristics, expression patterns, genetic variation, and regulation network. We identified a total of 77, 51, 29, and 30 ATGs in wheat, wild emmer, T. urartu and A. tauschii, respectively, and grouped them into 19 subfamilies. We found that these autophagy-related genes (ATGs) suffered various degrees of selection during the wheat’s domestication and breeding processes. The genetic variations in the promoter region of Ta2A_ATG8a were associated with differences in seed size, which might be artificially selected for during the domestication process of tetraploid wheat. Overexpression of TaVAMP727 improved the cold, drought, and salt stresses resistance of the transgenic Arabidopsis and wheat. It also promoted wheat heading by regulating the expression of most ATGs. Our findings demonstrate how ATGs regulate wheat plant development and improve abiotic stress resistance. The results presented here provide the basis for wheat breeding programs for selecting varieties of higher yield which are capable of growing in colder, drier, and saltier areas.

scholarly journals DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose

2015 ◽  
Vol 22 (10) ◽  
pp. 1714-1726 ◽  
Author(s):  
M Mrschtik ◽  
J O'Prey ◽  
L Y Lao ◽  
J S Long ◽  
F Beaumatin ◽  
...  
Keyword(s):  
Cell Survival ◽  
Membrane Trafficking ◽  
Clonogenic Survival ◽  
Autophagic Flux ◽  
Normal Tissues ◽  
Atg Proteins ◽  
Dna Damaging Agents ◽  
Evolutionarily Conserved ◽  
Starvation Conditions

Abstract Macroautophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. The process operates under basal conditions as a mechanism to turnover damaged or misfolded proteins and organelles. As a result, it has a major role in preserving cellular integrity and viability. In addition to this basal function, macroautophagy can also be modulated in response to various forms of cellular stress, and the rate and cargoes of macroautophagy can be tailored to facilitate appropriate cellular responses in particular situations. The macroautophagy machinery is regulated by a group of evolutionarily conserved autophagy-related (ATG) proteins and by several other autophagy regulators, which either have tissue-restricted expression or operate in specific contexts. We report here the characterization of a novel autophagy regulator that we have termed DRAM-3 due to its significant homology to damage-regulated autophagy modulator (DRAM-1). DRAM-3 is expressed in a broad spectrum of normal tissues and tumor cells, but different from DRAM-1, DRAM-3 is not induced by p53 or DNA-damaging agents. Immunofluorescence studies revealed that DRAM-3 localizes to lysosomes/autolysosomes, endosomes and the plasma membrane, but not the endoplasmic reticulum, phagophores, autophagosomes or Golgi, indicating significant overlap with DRAM-1 localization and with organelles associated with macroautophagy. In this regard, we further proceed to show that DRAM-3 expression causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Reciprocally, CRISPR/Cas9-mediated disruption of DRAM-3 impairs autophagic flux confirming that DRAM-3 is a modulator of macroautophagy. As macroautophagy can be cytoprotective under starvation conditions, we also tested whether DRAM-3 could promote survival on nutrient deprivation. This revealed that DRAM-3 can repress cell death and promote long-term clonogenic survival of cells grown in the absence of glucose. Interestingly, however, this effect is macroautophagy-independent. In summary, these findings constitute the primary characterization of DRAM-3 as a modulator of both macroautophagy and cell survival under starvation conditions.

Molecular evolution of the actin family

2002 ◽  
Vol 115 (13) ◽  
pp. 2619-2622 ◽  
Author(s):  
Holly V. Goodson ◽  
William F. Hawse
Keyword(s):  
Phylogenetic Analysis ◽  
Molecular Evolution ◽  
Chromatin Remodeling ◽  
The Core ◽  
Nuclear Process ◽  
Core Set ◽  
Eukaryotic Proteins ◽  
Related Proteins

Members of the actin family have well-characterized cytoskeletal functions,but actin and actin-related proteins (ARPs) have also been implicated in nuclear activities. Previous analyses of the actin family have identified four conserved subfamilies, but many actin-related proteins (ARPs) do not fall into these groups. A new systematic phylogenetic analysis reveals that at least eight ARP subfamilies are conserved from humans to yeast, indicating that these ARPs are part of the core set of eukaryotic proteins. Members of at least three subfamilies appear to be involved in chromatin remodeling,suggesting that ARPs play ancient, fundamental roles in this nuclear process.

A highly evolutionarily conserved mitochondrial protein is structurally related to the protein encoded by the Escherichia coli groEL gene

1988 ◽  
Vol 8 (1) ◽  
pp. 371-380
Author(s):  
T W McMullin ◽  
R L Hallberg
Keyword(s):  
Escherichia Coli ◽  
Tetrahymena Thermophila ◽  
Mitochondrial Protein ◽  
Cross Reactivity ◽  
Macromolecular Complexes ◽  
E Coli ◽  
Groel Gene ◽  
Evolutionarily Conserved ◽  
Associated Proteins ◽  
Related Proteins

We recently reported that a Tetrahymena thermophila 58-kilodalton (kDa) mitochondrial protein (hsp58) was selectively synthesized during heat shock. In this study, we show that hsp58 displayed antigenic similarity with mitochondrially associated proteins from Saccharomyces cerevisiae (64 kDa), Xenopus laevis (60 kDa), Zea mays (62 kDa), and human cells (59 kDa). Furthermore, a 58-kDa protein from Escherichia coli also exhibited antigenic cross-reactivity to an antiserum directed against the T. thermophila mitochondrial protein. The proteins from S. cerevisiae and E. coli antigenically related to hsp58 were studied in detail and found to share several other characteristics with hsp58, including heat inducibility and the property of associating into distinct oligomeric complexes. The T. thermophila, S. cerevisiae, and E. coli macromolecular complexes containing these related proteins had similar sedimentation characteristics and virtually identical morphologies as seen with the electron microscope. The distinctive properties of the E. coli homolog to T. thermophila hsp58 indicate that it is most likely the product of the groEL gene.

scholarly journals Autophagosome biogenesis: From membrane growth to closure

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Thomas J. Melia ◽  
Alf H. Lystad ◽  
Anne Simonsen
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Membrane Vesicle ◽  
Double Membrane ◽  
The Core ◽  
Membrane Modeling ◽  
Membrane Growth ◽  
Initial Discovery ◽  
Insight Into ◽  
Key Questions

Autophagosome biogenesis involves de novo formation of a membrane that elongates to sequester cytoplasmic cargo and closes to form a double-membrane vesicle (an autophagosome). This process has remained enigmatic since its initial discovery >50 yr ago, but our understanding of the mechanisms involved in autophagosome biogenesis has increased substantially during the last 20 yr. Several key questions do remain open, however, including, What determines the site of autophagosome nucleation? What is the origin and lipid composition of the autophagosome membrane? How is cargo sequestration regulated under nonselective and selective types of autophagy? This review provides key insight into the core molecular mechanisms underlying autophagosome biogenesis, with a specific emphasis on membrane modeling events, and highlights recent conceptual advances in the field.

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