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Cells Nov 2022Eukaryotes utilize different communication strategies to coordinate processes between different cellular compartments either indirectly, through vesicular transport, or... (Review)
Review
Eukaryotes utilize different communication strategies to coordinate processes between different cellular compartments either indirectly, through vesicular transport, or directly, via membrane contact sites (MCSs). MCSs have been implicated in lipid metabolism, calcium signaling and the regulation of organelle biogenesis in various cell types. Several studies have shown that MCSs play a crucial role in the regulation of macroautophagy, an intracellular catabolic transport route that is characterized by the delivery of cargoes (proteins, protein complexes or aggregates, organelles and pathogens) to yeast and plant vacuoles or mammalian lysosomes, for their degradation and recycling into basic metabolites. Macroautophagy is characterized by the de novo formation of double-membrane vesicles called autophagosomes, and their biogenesis requires an enormous amount of lipids. MCSs appear to have a central role in this supply, as well as in the organization of the autophagy-related (ATG) machinery. In this review, we will summarize the evidence for the participation of specific MCSs in autophagosome formation, with a focus on the budding yeast and mammalian systems.
Topics: Animals; Endoplasmic Reticulum; Autophagosomes; Autophagy; Lysosomes; Saccharomyces cerevisiae; Mammals
PubMed: 36497073
DOI: 10.3390/cells11233813 -
Developmental Cell Dec 2023The sequence of morphological intermediates that leads to mammalian autophagosome formation and closure is a crucial yet poorly understood issue. Previous studies have...
The sequence of morphological intermediates that leads to mammalian autophagosome formation and closure is a crucial yet poorly understood issue. Previous studies have shown that yeast autophagosomes evolve from cup-shaped phagophores with only one closure point, and mammalian studies have inferred that mammalian phagophores also have single openings. Our superresolution microscopy studies in different human cell lines in conditions of basal and nutrient-deprivation-induced autophagy identified autophagosome precursors with multifocal origins that evolved into unexpected finger-like phagophores with multiple openings before becoming more spherical structures. Compatible phagophore structures were observed with whole-mount and conventional electron microscopy. This sequence of events was visualized using advanced SIM superresolution live microscopy. The finger-shaped phagophore apertures remained open when ESCRT function was compromised. The efficient closure of autophagic structures is important for their release from the recycling endosome. This has important implications for understanding how autophagosomes form and capture various cargoes.
Topics: Animals; Humans; Autophagosomes; Autophagy; Endosomes; Cell Line; Phagocytosis; Mammals
PubMed: 37683632
DOI: 10.1016/j.devcel.2023.08.016 -
Cells Aug 2021Autophagy is a conserved self-degradation process that is activated under a wide variety of stresses and physiological conditions [...].
Autophagy is a conserved self-degradation process that is activated under a wide variety of stresses and physiological conditions [...].
Topics: Animals; Apoptosis; Autophagosomes; Autophagy; Autophagy-Related Proteins; Humans; Signal Transduction
PubMed: 34440756
DOI: 10.3390/cells10081987 -
Autophagy Jan 2023During macroautophagy/autophagy, autophagosomes fuse with lysosomes to form autolysosomes. After fusion, the autophagosome inner membrane and enclosed substrates are...
During macroautophagy/autophagy, autophagosomes fuse with lysosomes to form autolysosomes. After fusion, the autophagosome inner membrane and enclosed substrates are degraded and transported out of lysosomes for recycling. The lysosomal membrane components are recycled by autophagic lysosome reformation (ALR) to generate new lysosomes. However, the fate of autophagosome outer membrane components on autolysosomes remains unknown. Our recent work discovered that autophagosome outer membrane components are not degraded but are recycled through an unidentified process which we named autophagosomal components recycling (ACR). Further investigation revealed the recycler complex (SNX4-SNX5-SNX17) responsible for ACR. The discovery of ACR not only fills a missing part in autophagy, but also reveals a new recycling pathway on autolysosomes.
Topics: Autophagy; Autophagosomes; Intracellular Membranes; Macroautophagy; Lysosomes; Membrane Fusion
PubMed: 35635187
DOI: 10.1080/15548627.2022.2083807 -
Cells Oct 2021Autophagy is an evolutionarily conserved pathway, in which cytoplasmic components are sequestered within double-membrane vesicles called autophagosomes and then... (Review)
Review
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.
Topics: Animals; Autophagosomes; Calcium; Endosomal Sorting Complexes Required for Transport; Humans; SNARE Proteins; Sphingomyelins; rab GTP-Binding Proteins
PubMed: 34831036
DOI: 10.3390/cells10112814 -
Biochemical Society Transactions Feb 2022Macroautophagy, hereafter autophagy, is a degradative process conserved among eukaryotes, which is essential to maintain cellular homeostasis. Defects in autophagy lead... (Review)
Review
Macroautophagy, hereafter autophagy, is a degradative process conserved among eukaryotes, which is essential to maintain cellular homeostasis. Defects in autophagy lead to numerous human diseases, including various types of cancer and neurodegenerative disorders. The hallmark of autophagy is the de novo formation of autophagosomes, which are double-membrane vesicles that sequester and deliver cytoplasmic materials to lysosomes/vacuoles for degradation. The mechanism of autophagosome biogenesis entered a molecular era with the identification of autophagy-related (ATG) proteins. Although there are many unanswered questions and aspects that have raised some controversies, enormous advances have been done in our understanding of the process of autophagy in recent years. In this review, we describe the current knowledge about the molecular regulation of autophagosome formation, with a particular focus on budding yeast and mammalian cells.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Proteins; Humans; Lysosomes; Macroautophagy; Mammals
PubMed: 35076688
DOI: 10.1042/BST20210819 -
Autophagy Nov 2021It would be quite convenient if every protein had one distinct function, one distinct role in just a single cellular process. In the field of macroautophagy/autophagy,...
It would be quite convenient if every protein had one distinct function, one distinct role in just a single cellular process. In the field of macroautophagy/autophagy, however, we are increasingly finding that this is not the case; several autophagy proteins have two or more roles within the process of autophagy and many even "moonlight" as functional members of entirely different cellular processes. This is perhaps best exemplified by the Atg8-family proteins. These dynamic proteins have already been reported to serve several functions both within autophagy (membrane tethering, membrane fusion, binding to cargo receptors, binding to autophagy machinery) and beyond (LC3-associated phagocytosis, formation of EDEMosomes, immune signaling) but as Maruyama and colleagues suggest in their recent report, this list of functions may not yet be complete.
Topics: Animals; Autophagosomes; Autophagy; Autophagy-Related Protein 8 Family; Binding Sites; Humans; Models, Molecular; Molecular Docking Simulation; Mutation
PubMed: 34482799
DOI: 10.1080/15548627.2021.1967566 -
Plant Physiology Jan 2018Environmental stress activates autophagy and leads to autophagosome formation at the endoplasmic reticulum. (Review)
Review
Environmental stress activates autophagy and leads to autophagosome formation at the endoplasmic reticulum.
Topics: Autophagosomes; Autophagy; Cell Membrane; Models, Biological
PubMed: 29061903
DOI: 10.1104/pp.17.01236 -
Journal of Molecular Biology May 2016Selective autophagy contributes to intracellular homeostasis by mediating the degradation of cytoplasmic material such as aggregated proteins, damaged or over-abundant... (Review)
Review
Selective autophagy contributes to intracellular homeostasis by mediating the degradation of cytoplasmic material such as aggregated proteins, damaged or over-abundant organelles, and invading pathogens. The molecular machinery for selective autophagy must ensure efficient recognition and sequestration of the cargo within autophagosomes. Cargo specificity can be mediated by autophagic cargo receptors that specifically bind the cargo material and the autophagosomal membrane. Here we review the recent insights into the mechanisms that enable cargo receptors to confer selectivity and exclusivity to the autophagic process. We also discuss their different roles during starvation-induced and selective autophagy. We propose to classify autophagic events into cargo-independent and cargo-induced autophagosome formation events.
Topics: Autophagosomes; Autophagy; Homeostasis
PubMed: 26876603
DOI: 10.1016/j.jmb.2016.02.004 -
The Journal of Cell Biology Aug 2023Autophagy is a conserved and tightly regulated intracellular quality control pathway. ULK is a key kinase in autophagy initiation, but whether ULK kinase activity also...
Autophagy is a conserved and tightly regulated intracellular quality control pathway. ULK is a key kinase in autophagy initiation, but whether ULK kinase activity also participates in the late stages of autophagy remains unknown. Here, we found that the autophagosomal SNARE protein, STX17, is phosphorylated by ULK at residue S289, beyond which it localizes specifically to autophagosomes. Inhibition of STX17 phosphorylation prevents such autophagosome localization. FLNA was then identified as a linker between ATG8 family proteins (ATG8s) and STX17 with essential involvement in STX17 recruitment to autophagosomes. Phosphorylation of STX17 S289 promotes its interaction with FLNA, activating its recruitment to autophagosomes and facilitating autophagosome-lysosome fusion. Disease-causative mutations around the ATG8s- and STX17-binding regions of FLNA disrupt its interactions with ATG8s and STX17, inhibiting STX17 recruitment and autophagosome-lysosome fusion. Cumulatively, our study reveals an unexpected role of ULK in autophagosome maturation, uncovers its regulatory mechanism in STX17 recruitment, and highlights a potential association between autophagy and FLNA.
Topics: Autophagosomes; Autophagy; Autophagy-Related Protein 8 Family; Macroautophagy; Phosphorylation; Humans; Qa-SNARE Proteins; Filamins
PubMed: 37389864
DOI: 10.1083/jcb.202211025