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Molecular Cell Apr 2022As one of the two highly conserved cellular degradation systems, autophagy plays a critical role in regulation of protein, lipid, and organelle quality control and... (Review)
Review
As one of the two highly conserved cellular degradation systems, autophagy plays a critical role in regulation of protein, lipid, and organelle quality control and cellular homeostasis. This evolutionarily conserved pathway singles out intracellular substrates for elimination via encapsulation within a double-membrane vesicle and delivery to the lysosome for degradation. Multiple cancers disrupt normal regulation of autophagy and hijack its degradative ability to remodel their proteome, reprogram their metabolism, and adapt to environmental challenges, making the autophagy-lysosome system a prime target for anti-cancer interventions. Here, we discuss the roles of autophagy in tumor progression, including cancer-specific mechanisms of autophagy regulation and the contribution of tumor and host autophagy in metabolic regulation, immune evasion, and malignancy. We further discuss emerging proteomics-based approaches for systematic profiling of autophagosome-lysosome composition and contents. Together, these approaches are uncovering new features and functions of autophagy, leading to more effective strategies for targeting this pathway in cancer.
Topics: Autophagosomes; Autophagy; Humans; Lysosomes; Neoplasms; Quality Control
PubMed: 35452618
DOI: 10.1016/j.molcel.2022.03.023 -
Autophagy Jul 2023Autophagosome isolation enables the thorough investigation of structural components and engulfed materials. Recently, we introduced a novel antibody-based FACS-mediated...
Autophagosome isolation enables the thorough investigation of structural components and engulfed materials. Recently, we introduced a novel antibody-based FACS-mediated method for isolation of native macroautophagic/autophagic vesicles and confirmed the quality of the preparations. We performed phospholipidomic and proteomic analyses to characterize autophagic vesicle-associated phospholipids and protein cargoes under different autophagy conditions. Lipidomic analyses identified phosphoglycerides and sphingomyelins within autophagic vesicles and revealed that the lipid composition was unaffected by different rates of autophagosome formation. Proteomic analyses identified more than 4500 potential autophagy substrates and showed that in comparison to autophagic vesicles isolated under basal autophagy conditions, starvation only marginally affected the cargo profile. Proteasome inhibition, however, resulted in the enhanced degradation of ubiquitin-proteasome system components. Taken together, the novel isolation method enriched large quantities of autophagic vesicles and enabled detailed analyses of their lipid and cargo composition.
Topics: Autophagy; Proteasome Endopeptidase Complex; Proteomics; Autophagosomes; Lipids
PubMed: 36416088
DOI: 10.1080/15548627.2022.2151188 -
Future Medicinal Chemistry Mar 2021
Topics: Autophagosomes; Autophagy; Humans; Lysosomes; Proteins; Proteolysis; Small Molecule Libraries
PubMed: 33438469
DOI: 10.4155/fmc-2020-0343 -
Autophagy Aug 2020A key feature of macroautophagy (hereafter autophagy) is the formation of the phagophore, a double-membrane compartment sequestering cargos and finally maturing into a...
A key feature of macroautophagy (hereafter autophagy) is the formation of the phagophore, a double-membrane compartment sequestering cargos and finally maturing into a vesicle termed an autophagosome; however, where these membranes originate from is not clear. In a previous study, researchers from the Rubinsztein lab proposed a model in which the autophagosome can evolve from the RAB11A-positive recycling endosome. In their recent paper, they determine that DNM2 (dynamin 2) functions in scission of the recycling endosome, and the release of the autophagosome precursor. These findings explain how the centronuclear myopathy (CNM) mutation in DNM2 results in the accumulation of immature autophagic structures.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Proteins; Cell Membrane; Dynamin II; Endosomes; Humans; Mice; Mutation; Phenotype
PubMed: 32544363
DOI: 10.1080/15548627.2020.1779468 -
Annual Review of Cell and Developmental... Oct 2019Macroautophagy is an intracellular degradation system that delivers diverse cytoplasmic materials to lysosomes via autophagosomes. Recent advances have enabled... (Review)
Review
Macroautophagy is an intracellular degradation system that delivers diverse cytoplasmic materials to lysosomes via autophagosomes. Recent advances have enabled identification of several selective autophagy substrates and receptors, greatly expanding our understanding of the cellular functions of autophagy. In this review, we describe the diverse cellular functions of macroautophagy, including its essential contribution to metabolic adaptation and cellular homeostasis. We also discuss emerging findings on the mechanisms and functions of various types of selective autophagy.
Topics: Animals; Autophagosomes; Autophagy; Endoplasmic Reticulum; Homeostasis; Humans; Lysosomes; Mitochondria; Nutrients; Peroxisomes
PubMed: 31283377
DOI: 10.1146/annurev-cellbio-100818-125300 -
FEBS Letters Nov 2019Autophagy is widely considered as a housekeeping mechanism that enables cells to survive stress conditions and, in particular, nutrient deprivation. Autophagy begins... (Review)
Review
Autophagy is widely considered as a housekeeping mechanism that enables cells to survive stress conditions and, in particular, nutrient deprivation. Autophagy begins with the formation of the phagophore that expands and closes around cytosolic material and damaged organelles destined for degradation. The execution of this complex machinery is guaranteed by the coordinated action of more than 40 ATG (autophagy-related) proteins that control the entire process at different stages from the biogenesis of the autophagosome to cargo sequestration and fusion with lysosomes. Autophagosome biogenesis occurs at multiple intracellular sites, such as the endoplasmic reticulum (ER) and the plasma membrane. Soon after the formation of the phagophore, the nascent autophagosome progressively grows in size and ultimately closes by recruiting intracellular membranes. In this review, we focus on the contribution of three membrane sources - the ER, the ER-Golgi intermediate compartment, and the Golgi complex - to autophagosome biogenesis and expansion. We also highlight the interplay between the secretory pathway and autophagy in cells when nutrients are scarce.
Topics: Animals; Autophagosomes; Autophagy-Related Proteins; Endoplasmic Reticulum; Golgi Apparatus; Humans; Intracellular Membranes; Lysosomes
PubMed: 31603532
DOI: 10.1002/1873-3468.13637 -
The Journal of Clinical Investigation Jun 2020Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by...
Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by autophagy from death with autophagy, and whether autophagy contributes to death in cardiomyocytes (CMs) is still controversial. Excessive activation of autophagy induces a morphologically and biochemically defined form of cell death termed autosis. Whether autosis is involved in tissue injury induced under pathologically relevant conditions is poorly understood. In the present study, myocardial ischemia/reperfusion (I/R) induced autosis in CMs, as evidenced by cell death with numerous vacuoles and perinuclear spaces, and depleted intracellular membranes. Autosis was observed frequently after 6 hours of reperfusion, accompanied by upregulation of Rubicon, attenuation of autophagic flux, and marked accumulation of autophagosomes. Genetic downregulation of Rubicon inhibited autosis and reduced I/R injury, whereas stimulation of autosis during the late phase of I/R with Tat-Beclin 1 exacerbated injury. Suppression of autosis by ouabain, a cardiac glycoside, in humanized Na+,K+-ATPase-knockin mice reduced I/R injury. Taken together, these results demonstrate that autosis is significantly involved in I/R injury in the heart and triggered by dysregulated accumulation of autophagosomes due to upregulation of Rubicon.
Topics: Animals; Autophagosomes; Autophagy; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Myocardial Reperfusion Injury; Myocardium; Up-Regulation
PubMed: 32364533
DOI: 10.1172/JCI132366 -
Nature Communications Sep 2023In autophagy, a membrane cisterna called the isolation membrane expands, bends, becomes spherical, and closes to sequester cytoplasmic constituents into the resulting...
In autophagy, a membrane cisterna called the isolation membrane expands, bends, becomes spherical, and closes to sequester cytoplasmic constituents into the resulting double-membrane vesicle autophagosome for lysosomal/vacuolar degradation. Here, we discover a mechanism that allows the isolation membrane to expand with a large opening to ensure non-selective cytoplasm sequestration within the autophagosome. A sorting nexin complex that localizes to the opening edge of the isolation membrane plays a critical role in this process. Without the complex, the isolation membrane expands with a small opening that prevents the entry of particles larger than about 25 nm, including ribosomes and proteasomes, although autophagosomes of nearly normal size eventually form. This study sheds light on membrane morphogenesis during autophagosome formation and selectivity in autophagic degradation.
Topics: Autophagy; Autophagosomes; Cytosol; Macroautophagy; Ribosomes
PubMed: 37726301
DOI: 10.1038/s41467-023-41525-x -
Molecular Cancer Jan 2024Eukaryotic cells engage in autophagy, an internal process of self-degradation through lysosomes. Autophagy can be classified as selective or non-selective depending on... (Review)
Review
Eukaryotic cells engage in autophagy, an internal process of self-degradation through lysosomes. Autophagy can be classified as selective or non-selective depending on the way it chooses to degrade substrates. During the process of selective autophagy, damaged and/or redundant organelles like mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes, and lipid droplets are selectively recycled. Specific cargo is delivered to autophagosomes by specific receptors, isolated and engulfed. Selective autophagy dysfunction is closely linked with cancers, neurodegenerative diseases, metabolic disorders, heart failure, etc. Through reviewing latest research, this review summarized molecular markers and important signaling pathways for selective autophagy, and its significant role in cancers. Moreover, we conducted a comprehensive analysis of small-molecule compounds targeting selective autophagy for their potential application in anti-tumor therapy, elucidating the underlying mechanisms involved. This review aims to supply important scientific references and development directions for the biological mechanisms and drug discovery of anti-tumor targeting selective autophagy in the future.
Topics: Humans; Autophagy; Neoplasms; Autophagosomes; Cell Nucleus; Drug Discovery
PubMed: 38262996
DOI: 10.1186/s12943-024-01934-y -
Autophagy Mar 2024Macroautophagy/autophagy is a highly conserved process that involves the degradation of proteins, damaged organelles, and other cytoplasmic macromolecules....
Macroautophagy/autophagy is a highly conserved process that involves the degradation of proteins, damaged organelles, and other cytoplasmic macromolecules. Autophagosome-lysosome fusion is critical for successful substrate degradation and is mediated by SNARE proteins. The fusion process requires additional vesicle docking and tethering-regulating factors. Our recent work has uncovered a functional model of autophagosome-lysosome fusion. We demonstrated that the six-subunit homotypic fusion and vacuole protein sorting (HOPS) complex can be assembled by two subcomplexes, the VPS39-VPS11 subcomplex (HOPS-2) and the VPS41-VPS16-VPS18-VPS33A subcomplex (HOPS-4). VPS39 binds with RAB2 on the autophagosome and VPS41 binds with RAB39A on the lysosome, which then promotes membrane tethering and autophagic SNARE-mediated membrane fusion. Moreover, we have revealed that ALS- and FTD-related C9orf72 is a guanine exchange factor (GEF) for RAB39A. In this punctum, we discuss how the C9orf72-RAB39A-HOPS axis function regulates autophagosome-lysosome fusion.
Topics: Macroautophagy; C9orf72 Protein; Autophagy; Autophagosomes; Membrane Fusion; SNARE Proteins; Lysosomes
PubMed: 38083843
DOI: 10.1080/15548627.2023.2291938