scholarly journals Autophagy and Exosomes Relationship in Cancer: Friends or Foes?

2021 ◽  
Vol 8 ◽  
Author(s):  
Marta Colletti ◽  
Donatella Ceglie ◽  
Angela Di Giannatale ◽  
Francesca Nazio
Keyword(s):  
Membrane Vesicle ◽  
Cancer Therapeutics ◽  
Degradation Process ◽  
Regulatory Mechanisms ◽  
Clinical Implications ◽  
Double Membrane ◽  
Intracellular Degradation ◽  
Cancer Initiation ◽  
Pathway Interaction ◽  
Molecular Machinery

Autophagy is an intracellular degradation process involved in the removal of proteins and damaged organelles by the formation of a double-membrane vesicle named autophagosome and degraded through fusion with lysosomes. An intricate relationship between autophagy and the endosomal and exosomal pathways can occur at different stages with important implications for normal physiology and human diseases. Recent researches have revealed that extracellular vesicles (EVs), such as exosomes, could have a cytoprotective role by inducing intracellular autophagy; on the other hand, autophagy plays a crucial role in the biogenesis and degradation of exosomes. Although the importance of these processes in cancer is well established, their interplay in tumor is only beginning to be documented. In some tumor contexts (1) autophagy and exosome-mediated release are coordinately activated, sharing the molecular machinery and regulatory mechanisms; (2) cancer cell-released exosomes impact on autophagy in recipient cells through mechanisms yet to be determined; (3) exosome-autophagy relationship could affect drug resistance and tumor microenvironment (TME). In this review, we survey emerging discoveries relevant to the exosomes and autophagy crosstalk in the context of cancer initiation, progression and recurrence. Consequently, we discuss clinical implications by targeting autophagy-exosomal pathway interaction and how this could lay a basis for the purpose of novel cancer therapeutics.

scholarly journals The Autophagy Machinery in Human-Parasitic Protists; Diverse Functions for Universally Conserved Proteins

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1258
Author(s):  
Hirokazu Sakamoto ◽  
Kumiko Nakada-Tsukui ◽  
Sébastien Besteiro
Keyword(s):  
Membrane Vesicle ◽  
Model Organisms ◽  
Unicellular Eukaryotes ◽  
Current State ◽  
Important Challenge ◽  
Molecular Machinery ◽  
Cellular Machinery ◽  
Apparent Reduction ◽  
Related Proteins ◽  
Genome Projects

Autophagy is a eukaryotic cellular machinery that is able to degrade large intracellular components, including organelles, and plays a pivotal role in cellular homeostasis. Target materials are enclosed by a double membrane vesicle called autophagosome, whose formation is coordinated by autophagy-related proteins (ATGs). Studies of yeast and Metazoa have identified approximately 40 ATGs. Genome projects for unicellular eukaryotes revealed that some ATGs are conserved in all eukaryotic supergroups but others have arisen or were lost during evolution in some specific lineages. In spite of an apparent reduction in the ATG molecular machinery found in parasitic protists, it has become clear that ATGs play an important role in stage differentiation or organelle maintenance, sometimes with an original function that is unrelated to canonical degradative autophagy. In this review, we aim to briefly summarize the current state of knowledge in parasitic protists, in the light of the latest important findings from more canonical model organisms. Determining the roles of ATGs and the diversity of their functions in various lineages is an important challenge for understanding the evolutionary background of autophagy.

Autophagy is required during high MUC2 mucin biosynthesis in colonic goblet cells to contend metabolic stress

2021 ◽  
Author(s):  
Sameer Tiwari ◽  
Sharmin Begum ◽  
France Moreau ◽  
Hayley Gorman ◽  
Kris Chadee
Keyword(s):  
Endoplasmic Reticulum ◽  
Essential Role ◽  
Metabolic Stress ◽  
Thick Layer ◽  
Degradation Process ◽  
Goblet Cells ◽  
Mucosal Epithelium ◽  
Intracellular Degradation ◽  
Muc2 Expression ◽  
Or Gene

Goblet cells are specialized for the production and secretion of MUC2 glycoproteins that forms a thick layer covering the mucosal epithelium as a protective barrier against noxious substances and invading microbes. High MUC2 mucin biosynthesis induces endoplasmic reticulum (ER) stress and apoptosis in goblet cells during inflammatory and infectious diseases. Autophagy is an intracellular degradation process required for maintenance of intestinal homeostasis. In this study, we hypothesized that autophagy was triggered during high MUC2 mucin biosynthesis from colonic goblet cells to cope with metabolic stress. To interrogate this, we analyzed the autophagy process in high MUC2-producing human HT29-H and a clone HT29-L silenced for MUC2 expression by lentivirus-mediated shRNA, and WT and CRISPR/Cas9 MUC2 KO LS174T cells. Autophagy was constitutively increased in high MUC2 producing cells characterized by elevated pULK1S555 expression and increased numbers of autophagosomes as compared to MUC2 silenced or gene edited cells. Similarly, colonoids from Muc2+/+ but not Muc2-/- littermates differentiated into goblet cells showed increased autophagy. IL-22 treatment corrected misfolded MUC2 protein and alleviated the autophagy process in LS174T cells. This study highlights that autophagy plays an essential role in goblet cells to survive during high mucin biosynthesis by regulating cellular homeostasis.

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.

scholarly journals A molecular pore spans the double membrane of the coronavirus replication organelle

Science ◽  
2020 ◽  
Vol 369 (6509) ◽  
pp. 1395-1398 ◽  
Author(s):  
Georg Wolff ◽  
Ronald W. A. L. Limpens ◽  
Jessika C. Zevenhoven-Dobbe ◽  
Ulrike Laugks ◽  
Shawn Zheng ◽  
...  
Keyword(s):  
Drug Target ◽  
Rna Synthesis ◽  
Transmembrane Protein ◽  
Membrane Vesicle ◽  
Membrane Vesicles ◽  
Genome Replication ◽  
Messenger Rnas ◽  
Double Membrane ◽  
The Core ◽  
Cryo Electron Microscopy

Coronavirus genome replication is associated with virus-induced cytosolic double-membrane vesicles, which may provide a tailored microenvironment for viral RNA synthesis in the infected cell. However, it is unclear how newly synthesized genomes and messenger RNAs can travel from these sealed replication compartments to the cytosol to ensure their translation and the assembly of progeny virions. In this study, we used cellular cryo–electron microscopy to visualize a molecular pore complex that spans both membranes of the double-membrane vesicle and would allow export of RNA to the cytosol. A hexameric assembly of a large viral transmembrane protein was found to form the core of the crown-shaped complex. This coronavirus-specific structure likely plays a key role in coronavirus replication and thus constitutes a potential drug target.

scholarly journals The Role of Beclin 1-Dependent Autophagy in Cancer

Biology ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 4 ◽  
Author(s):  
Silvia Vega-Rubín-de-Celis
Keyword(s):  
Dna Damage ◽  
Tumor Suppression ◽  
Protein Aggregates ◽  
Degradation Process ◽  
Beclin 1 ◽  
Cancer Type ◽  
Intracellular Degradation

Autophagy (self-eating) is an intracellular degradation process used by cells to keep a “clean house”; as it degrades abnormal or damaged proteins and organelles, it helps to fight infections and also provides energy in times of fasting or exercising. Autophagy also plays a role in cancer, although its precise function in each cancer type is still obscure, and whether autophagy plays a protecting (through the clearing of damaged organelles and protein aggregates and preventing DNA damage) or a promoting (by fueling the already stablished tumor) role in cancer remains to be fully characterized. Beclin 1, the mammalian ortholog of yeast Atg6/Vps30, is an essential autophagy protein and has been shown to play a role in tumor suppression. Here, an update of the tumorigenesis regulation by Beclin 1-dependent autophagy is provided.

scholarly journals Recent Advances in Single-Particle Electron Microscopic Analysis of Autophagy Degradation Machinery

2020 ◽  
Vol 21 (21) ◽  
pp. 8051
Author(s):  
Yiu Wing Sunny Cheung ◽  
Sung-Eun Nam ◽  
Calvin K. Yip
Keyword(s):  
Single Particle ◽  
Membrane Vesicle ◽  
Microscopic Analysis ◽  
Degradation Process ◽  
Electron Microscopic ◽  
Major Pathway ◽  
Selective Autophagy ◽  
Selective Degradation ◽  
The Core ◽  
Atg Proteins

Macroautophagy (also known as autophagy) is a major pathway for selective degradation of misfolded/aggregated proteins and damaged organelles and non-selective degradation of cytoplasmic constituents for the generation of power during nutrient deprivation. The multi-step degradation process, from sequestering cytoplasmic cargo into the double-membrane vesicle termed autophagosome to the delivery of the autophagosome to the lysosome or lytic vacuole for breakdown, is mediated by the core autophagy machinery composed of multiple Atg proteins, as well as the divergent sequence family of selective autophagy receptors. Single-particle electron microscopy (EM) is a molecular imaging approach that has become an increasingly important tool in the structural characterization of proteins and macromolecular complexes. This article summarizes the contributions single-particle EM have made in advancing our understanding of the core autophagy machinery and selective autophagy receptors. We also discuss current technical challenges and roadblocks, as well as look into the future of single-particle EM in autophagy research.

scholarly journals MicroRNAs as Emerging Regulators of Signaling in the Tumor Microenvironment

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 911 ◽  
Author(s):  
Shahzad Nawaz Syed ◽  
Bernhard Brüne
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathways ◽  
Target Identification ◽  
Cancer Therapeutics ◽  
Protein Translation ◽  
Transcriptional Gene Silencing ◽  
Post Transcriptional Gene Silencing ◽  
Cancer Initiation ◽  
Regulate Protein

A myriad of signaling molecules in a heuristic network of the tumor microenvironment (TME) pose a challenge and an opportunity for novel therapeutic target identification in human cancers. MicroRNAs (miRs), due to their ability to affect signaling pathways at various levels, take a prominent space in the quest of novel cancer therapeutics. The role of miRs in cancer initiation, progression, as well as in chemoresistance, is being increasingly investigated. The canonical function of miRs is to target mRNAs for post-transcriptional gene silencing, which has a great implication in first-order regulation of signaling pathways. However, several reports suggest that miRs also perform non-canonical functions, partly due to their characteristic non-coding small RNA nature. Examples emerge when they act as ligands for toll-like receptors or perform second-order functions, e.g., to regulate protein translation and interactions. This review is a compendium of recent advancements in understanding the role of miRs in cancer signaling and focuses on the role of miRs as novel regulators of the signaling pathway in the TME.

scholarly journals The conserved oligomeric Golgi complex is involved in double-membrane vesicle formation during autophagy

2010 ◽  
Vol 188 (1) ◽  
pp. 101-114 ◽  
Author(s):  
Wei-Lien Yen ◽  
Takahiro Shintani ◽  
Usha Nair ◽  
Yang Cao ◽  
Brian C. Richardson ◽  
...  
Keyword(s):  
Membrane Vesicle ◽  
Autophagosome Formation ◽  
Double Membrane ◽  
Complex Part ◽  
Cog Complex ◽  
Conserved Oligomeric Golgi Complex ◽  
Conserved Oligomeric Golgi ◽  
Critical Components ◽  
Molecular Components ◽  
Related Proteins

Macroautophagy is a catabolic pathway used for the turnover of long-lived proteins and organelles in eukaryotic cells. The morphological hallmark of this process is the formation of double-membrane autophagosomes that sequester cytoplasm. Autophagosome formation is the most complex part of macroautophagy, and it is a dynamic event that likely involves vesicle fusion to expand the initial sequestering membrane, the phagophore; however, essentially nothing is known about this process including the molecular components involved in vesicle tethering and fusion. In this study, we provide evidence that the subunits of the conserved oligomeric Golgi (COG) complex are required for double-membrane cytoplasm to vacuole targeting vesicle and autophagosome formation. COG subunits localized to the phagophore assembly site and interacted with Atg (autophagy related) proteins. In addition, mutations in the COG genes resulted in the mislocalization of Atg8 and Atg9, which are critical components involved in autophagosome formation.

scholarly journals Pex3 confines pexophagy receptor activity of Atg36 to peroxisomes by regulating Hrr25-mediated phosphorylation and proteasomal degradation

2020 ◽  
Vol 295 (48) ◽  
pp. 16292-16298
Author(s):  
Sota Meguro ◽  
Xizhen Zhuang ◽  
Hiromi Kirisako ◽  
Hitoshi Nakatogawa
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Recombinant Proteins ◽  
Posttranslational Modifications ◽  
Membrane Vesicles ◽  
Proteasomal Degradation ◽  
Regulatory Mechanisms ◽  
Autophagosome Formation ◽  
Peroxisomal Membrane ◽  
Double Membrane ◽  
Selective Autophagy

In macroautophagy (hereafter autophagy), cytoplasmic molecules and organelles are randomly or selectively sequestered within double-membrane vesicles called autophagosomes and delivered to lysosomes or vacuoles for degradation. In selective autophagy, the specificity of degradation targets is determined by autophagy receptors. In the budding yeast Saccharomyces cerevisiae, autophagy receptors interact with specific targets and Atg11, resulting in the recruitment of a protein complex that initiates autophagosome formation. Previous studies have revealed that autophagy receptors are regulated by posttranslational modifications. In selective autophagy of peroxisomes (pexophagy), the receptor Atg36 localizes to peroxisomes by binding to the peroxisomal membrane protein Pex3. We previously reported that Atg36 is phosphorylated by Hrr25 (casein kinase 1δ), increasing the Atg36–Atg11 interaction and thereby stimulating pexophagy initiation. However, the regulatory mechanisms underlying Atg36 phosphorylation are unknown. Here, we show that Atg36 phosphorylation is abolished in cells lacking Pex3 or expressing a Pex3 mutant defective in the interaction with Atg36, suggesting that the interaction with Pex3 is essential for the Hrr25-mediated phosphorylation of Atg36. Using recombinant proteins, we further demonstrated that Pex3 directly promotes Atg36 phosphorylation by Hrr25. A co-immunoprecipitation analysis revealed that the interaction of Atg36 with Hrr25 depends on Pex3. These results suggest that Pex3 increases the Atg36–Hrr25 interaction and thereby stimulates Atg36 phosphorylation on the peroxisomal membrane. In addition, we found that Pex3 binding protects Atg36 from proteasomal degradation. Thus, Pex3 confines Atg36 activity to the peroxisome by enhancing its phosphorylation and stability on this organelle.

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