Omegasomes: PI3P platforms that manufacture autophagosomes

2013 ◽  
Vol 55 ◽  
pp. 17-27 ◽  
Author(s):  
Rebecca Roberts ◽  
Nicholas T. Ktistakis
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Membrane Vesicles ◽  
Double Membrane ◽  
Survival Pathway ◽  
Membrane Compartments ◽  
Specific Control ◽  
Phosphatidylinositol 3

Autophagy is a conserved survival pathway, which cells and tissues will activate during times of stress. It is characterized by the formation of double-membrane vesicles called autophagosomes inside the cytoplasm. The molecular mechanisms and the signalling components involved require specific control to ensure correct activation. The present chapter describes the formation of autophagosomes from within omegasomes, newly identified membrane compartments enriched in PI3P (phosphatidylinositol 3-phosphate) that serve as platforms for the formation of at least some autophagosomes. We discuss the signalling events required to nucleate the formation of omegasomes as well as the protein complexes involved.

scholarly journals Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum

2008 ◽  
Vol 182 (4) ◽  
pp. 685-701 ◽  
Author(s):  
Elizabeth L. Axe ◽  
Simon A. Walker ◽  
Maria Manifava ◽  
Priya Chandra ◽  
H. Llewelyn Roderick ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Dynamic Equilibrium ◽  
Membrane Vesicles ◽  
Amino Acid Starvation ◽  
Autophagosome Formation ◽  
Double Membrane ◽  
Dynamic Relationship ◽  
Golgi Membranes ◽  
Membrane Compartments ◽  
Phosphatidylinositol 3

Autophagy is the engulfment of cytosol and organelles by double-membrane vesicles termed autophagosomes. Autophagosome formation is known to require phosphatidylinositol 3-phosphate (PI(3)P) and occurs near the endoplasmic reticulum (ER), but the exact mechanisms are unknown. We show that double FYVE domain–containing protein 1, a PI(3)P-binding protein with unusual localization on ER and Golgi membranes, translocates in response to amino acid starvation to a punctate compartment partially colocalized with autophagosomal proteins. Translocation is dependent on Vps34 and beclin function. Other PI(3)P-binding probes targeted to the ER show the same starvation-induced translocation that is dependent on PI(3)P formation and recognition. Live imaging experiments show that this punctate compartment forms near Vps34-containing vesicles, is in dynamic equilibrium with the ER, and provides a membrane platform for accumulation of autophagosomal proteins, expansion of autophagosomal membranes, and emergence of fully formed autophagosomes. This PI(3)P-enriched compartment may be involved in autophagosome biogenesis. Its dynamic relationship with the ER is consistent with the idea that the ER may provide important components for autophagosome formation.

scholarly journals Mitochondria and Mitochondrial DNA: Key Elements in the Pathogenesis and Exacerbation of the Inflammatory State Caused by COVID-19

Medicina ◽  
2021 ◽  
Vol 57 (9) ◽  
pp. 928
Author(s):  
José J. Valdés-Aguayo ◽  
Idalia Garza-Veloz ◽  
José I. Badillo-Almaráz ◽  
Sofia Bernal-Silva ◽  
Maria C. Martínez-Vázquez ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Viral Genome ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Defense System ◽  
Mt Dna ◽  
Double Membrane ◽  
Cell Defense ◽  
Inflammatory State ◽  
Potential Area

Background and Objectives. The importance of mitochondria in inflammatory pathologies, besides providing energy, is associated with the release of mitochondrial damage products, such as mitochondrial DNA (mt-DNA), which may perpetuate inflammation. In this review, we aimed to show the importance of mitochondria, as organelles that produce energy and intervene in multiple pathologies, focusing mainly in COVID-19 and using multiple molecular mechanisms that allow for the replication and maintenance of the viral genome, leading to the exacerbation and spread of the inflammatory response. The evidence suggests that mitochondria are implicated in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which forms double-membrane vesicles and evades detection by the cell defense system. These mitochondrion-hijacking vesicles damage the integrity of the mitochondrion’s membrane, releasing mt-DNA into circulation and triggering the activation of innate immunity, which may contribute to an exacerbation of the pro-inflammatory state. Conclusions. While mitochondrial dysfunction in COVID-19 continues to be studied, the use of mt-DNA as an indicator of prognosis and severity is a potential area yet to be explored.

scholarly journals The Molecular Interplay between Human Coronaviruses and Autophagy

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2022
Author(s):  
Ankit Shroff ◽  
Taras Y. Nazarko
Keyword(s):  
Life Cycle ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Intracellular Protein ◽  
Double Membrane ◽  
The Past ◽  
Trafficking Pathway ◽  
Life Threatening ◽  
Human Coronaviruses

Coronavirus disease 2019 (COVID-19), caused by a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has instantaneously emerged as a worldwide pandemic. However, humans encountered other coronaviruses in the past, and they caused a broad range of symptoms, from mild to life-threatening, depending on the virus and immunocompetence of the host. Most human coronaviruses interact with the proteins and/or double-membrane vesicles of autophagy, the membrane trafficking pathway that degrades and recycles the intracellular protein aggregates, organelles, and pathogens, including viruses. However, coronaviruses often neutralize and hijack this pathway to complete their life cycle. In this review, we discuss the interactions of human coronaviruses and autophagy, including recent data from SARS-CoV-2-related studies. Some of these interactions (for example, viral block of the autophagosome–lysosome fusion), while being conserved across multiple coronaviruses, are accomplished via different molecular mechanisms. Therefore, it is important to understand the molecular interplay between human coronaviruses and autophagy for developing efficient therapies against coronaviral diseases.

scholarly journals Glycine-zipper motifs in hepatitis C virus nonstructural protein 4B are required for the establishment of viral replication organelles

2017 ◽  
pp. JVI.01890-17 ◽  
Author(s):  
David Paul ◽  
Vanesa Madan ◽  
Omar Ramirez ◽  
Maja Bencun ◽  
Ina Karen Stoeck ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Molecular Mechanisms ◽  
Nonstructural Protein ◽  
Membrane Vesicles ◽  
Rna Replication ◽  
Viral Rna ◽  
Transmembrane Helices ◽  
Double Membrane

Hepatitis C virus (HCV) RNA replication occurs in tight association with remodeled host cell membranes, presenting as cytoplasmic accumulations of single, double and multi membrane vesicles in infected cells. Formation of these so-called replication organelles is mediated by a complex interplay of host cell factors and viral replicase proteins. Of these, nonstructural protein 4B (NS4B), an integral transmembrane protein, appears to play a key role, but little is known about the molecular mechanisms how this protein contributes to organelle biogenesis. Using forward and reverse genetics we identified glycine-zipper motifs within transmembrane helices 2 and 3 of NS4B that are critically involved in viral RNA replication. Foerster resonance energy transfer analysis revealed the importance of the glycine-zippers in NS4B homo and heterotypic self-interactions. Additionally, ultrastructural analysis using electron microscopy unraveled a prominent role of glycine-zipper residues for the subcellular distribution and the morphology of HCV-induced double membrane vesicles. Notably, loss-of-function NS4B glycine-zipper mutants prominently induced single membrane vesicles with secondary invaginations that might represent an arrested intermediate state in double membrane vesicle formation. These findings highlight a so far unknown role of glycine residues within the membrane integral core domain for NS4B self-interaction and functional as well as structural integrity of HCV replication organelles.IMPORTANCERemodeling of the cellular endomembrane system leading to the establishment of replication organelles is a hallmark of positive-strand RNA viruses. In the case of hepatitis C virus (HCV), expression of the nonstructural proteins induces the accumulation of double membrane vesicles that likely arise from a concerted action of viral and co-opted cellular factors. However, the underlying molecular mechanisms are incompletely understood. Here, we identify glycine-zipper motifs within HCV nonstructural protein 4B (NS4B) transmembrane segments 2 and 3 that are crucial for the protein's self-interaction. Moreover, glycine residues within NS4B transmembrane helices critically contribute to the biogenesis of functional replication organelles and thus, efficient viral RNA replication. These results reveal how glycine-zipper motifs in NS4B contribute to structural and functional integrity of the HCV replication organelles and thus, viral RNA replication.

scholarly journals Autophagy regulation by acetylation—implications for neurodegenerative diseases

2021 ◽  
Vol 53 (1) ◽  
pp. 30-41
Author(s):  
Sung Min Son ◽  
So Jung Park ◽  
Marian Fernandez-Estevez ◽  
David C. Rubinsztein
Keyword(s):  
Neurodegenerative Diseases ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Double Membrane ◽  
Physiological Processes ◽  
Evolutionarily Conserved ◽  
Development And Aging ◽  
Catabolic Process

AbstractPosttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions.

scholarly journals Transcriptome and proteome analysis suggest enhanced photosynthesis in tetraploid Liriodendron sino-americanum

2021 ◽  
Author(s):  
Tingting Chen ◽  
Yu Sheng ◽  
Zhaodong Hao ◽  
Xiaofei Long ◽  
Fangfang Fu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Proteome Analysis ◽  
Tree Height ◽  
Photosynthetic Electron Transport ◽  
Industrial Applications ◽  
Chlorophyll Protein Complexes ◽  
Chlorophyll Protein ◽  
Photosynthesis Genes ◽  
Underlying Mechanisms

Abstract Polyploidy generally provides an advantage in phenotypic variation and growth vigor. However, the underlying mechanisms remain poorly understood. The tetraploid L. sino-americanum exhibits altered morphology compared to its diploid counterpart, including larger, thicker and deeper green leaves, bigger stomata, thicker stems and increased tree height. Such characteristics can be useful in ornamental and industrial applications. To elucidate the molecular mechanisms behind this variation, we performed a comparative transcriptome and proteome analysis. Our transcriptome data indicated that some photosynthesis genes and pathways were differentially altered and enriched in tetraploid L. sino-americanum, mainly related to F-type ATPase, the cytochrome b6/f complex, photosynthetic electron transport, the light harvesting chlorophyll protein complexes, photosystem I and II. Most of the differentially expressed proteins we could identify are also involved in photosynthesis. Our physiological results showed that tetraploids have an enhanced photosynthetic capacity, concomitant with great levels of sugar and starch in leaves. This suggests that tetraploid L. sino-americanum might experience comprehensive transcriptome reprogramming of genes related to photosynthesis. This study has especially emphasized molecular changes involved in photosynthesis that accompany polyploidy, and provides a possible explanation for the altered phenotype of polyploidy plants in comparison to their diploid form.

Molecular Mechanisms Underlying the Anti-Breast Cancer Stem Cell Activity of Pterocladia capillacea and Corallina officinalis Polysaccharides

2021 ◽  
Vol 21 ◽  
Author(s):  
Hebatallah G. Hafez ◽  
Rafat M. Mohareb ◽  
Sohair M. Salem ◽  
Azza A. Matloub ◽  
Emad F. Eskander ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Cell Activity ◽  
Sulfated Polysaccharide ◽  
Corallina Officinalis ◽  
Stem Cell Activity ◽  
Mcf 7

Objective: This study aimed to appraise the activity of Pterocladia capillacea and Corallina officinalis polysaccharides against breast cancer stem cells (BCSCs). P. capillacea and C. officinalis polysaccharides were characterized to be sulfated polysaccharide-protein complexes. Methods: Cytotoxicity of the polysaccharides against MDA-MB-231 and MCF-7 cell lines along with their impact on CD44+/CD24− and aldehyde dehydrogenase 1(ALDH1) positive BCSC population were determined. Their effect on gene expression of CSC markers, Wnt/β-catenin and Notch signaling pathways was evaluated. Results: P. capillacea and C. officinalis polysaccharides inhibited the growth of breast cancer cells and reduced BCSC subpopulation. P. capillacea polysaccharides significantly down-regulated OCT4, SOX2, ALDH1A3 and vimentin in MDA-MB-231 as well as in MCF-7 cells except for vimentin that was up-regulated in MCF-7 cells. C. officinalis polysaccharides exhibited similar effects except for OCT4 that was up-regulated in MDA-MB-231 cells. Significant suppression of Cyclin D1 gene expression was noted in MDA-MB-231 and MCF-7 cells treated with P. capillacea or C. officinalis polysaccharides. β-catenin and c-Myc genes were significantly down-regulated in MDA-MB-231 cells treated with C. officinalis and P. capillacea polysaccharides, respectively, while being up-regulated in MCF-7 cells treated with either of them. Additionally, P. capillacea and C. officinalis polysaccharides significantly down-regulated Hes1 gene in MCF-7 cells despite increasing Notch1 gene expression level. However, significant down-regulation of Notch1 gene was observed in MDA-MB-231 cells treated with P. capillacea polysaccharides. Conclusion: Collectively, this study provides evidence for the effectiveness of P. capillacea and C. officinalis polysaccharides in targeting BCSCs through interfering with substantial signaling pathways contributing to their functionality.

scholarly journals Genome-wide interrogation of extracellular vesicle biology using barcoded miRNAs

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Albert Lu ◽  
Paulina Wawro ◽  
David W Morgens ◽  
Fernando Portela ◽  
Michael C Bassik ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Extracellular Vesicle ◽  
Biologically Active ◽  
Vesicle Release ◽  
Guide Rnas ◽  
Disease States ◽  
Genome Wide ◽  
First Time

Extracellular vesicles mediate transfer of biologically active molecules between neighboring or distant cells, and these vesicles may play important roles in normal physiology and the pathogenesis of multiple disease states including cancer. However, the underlying molecular mechanisms of their biogenesis and release remain unknown. We designed artificially barcoded, exosomal microRNAs (bEXOmiRs) to monitor extracellular vesicle release quantitatively using deep sequencing. We then expressed distinct pairs of CRISPR guide RNAs and bEXOmiRs, enabling identification of genes influencing bEXOmiR secretion from Cas9-edited cells. This approach uncovered genes with unrecognized roles in multivesicular endosome exocytosis, including critical roles for Wnt signaling in extracellular vesicle release regulation. Coupling bEXOmiR reporter analysis with CRISPR-Cas9 screening provides a powerful and unbiased means to study extracellular vesicle biology and for the first time, to associate a nucleic acid tag with individual membrane vesicles.

scholarly journals Updating the NLRC4 Inflammasome: from Bacterial Infections to Autoimmunity and Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiexia Wen ◽  
Bin Xuan ◽  
Yang Liu ◽  
Liwei Wang ◽  
Li He ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Immune Defense ◽  
Innate Immune ◽  
Sensor Protein ◽  
Different Types ◽  
Microbial Infections ◽  
Activation Mechanisms ◽  
Specific Protease

Inflammasomes comprise a family of cytosolic multi-protein complexes that modulate the activation of cysteine-aspartate-specific protease 1 (caspase-1) and promote the maturation and secretion of interleukin (IL)-1β and IL-18, leading to an inflammatory response. Different types of inflammasomes are defined by their sensor protein which recognizes pathogenic ligands and then directs inflammasome assembly. Although the specific molecular mechanisms underlying the activation of most inflammasomes are still unclear, NLRC4 inflammasomes have emerged as multifaceted agents of the innate immune response, playing important roles in immune defense against a variety of pathogens. Other studies have also expanded the scope of NLRC4 inflammasomes to include a range of inherited human autoimmune diseases as well as proposed roles in cancer. In this review article, we provide an updated overview of NLRC4 inflammasomes, describing their composition, activation mechanisms and roles in both microbial infections and other disease conditions.

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