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Proceedings of the Japan Academy.... 2020Autophagy is an intracellular degradation system that is present in most eukaryotes. In the process of autophagy, double membrane vesicles called autophagosomes... (Review)
Review
Autophagy is an intracellular degradation system that is present in most eukaryotes. In the process of autophagy, double membrane vesicles called autophagosomes sequester a wide variety of cellular constituents and deliver them to lytic organelles: lysosomes in mammals and vacuoles in yeast and plants. Although autophagy used to be considered a non-selective process in its target sequestration into autophagosomes, recent studies have revealed that autophagosomes can also selectively sequester certain proteins and organelles that have become unnecessary or harmful for the cell. We recently discovered that the endoplasmic reticulum (ER) is degraded by autophagy in a selective manner in the budding yeast Saccharomyces cerevisiae, and identified "receptor proteins" that play pivotal roles in this "ER-phagy" pathway. Moreover, several ER-phagy receptors in mammalian cells have also been reported. This report provides an overview of our current knowledge on ER-phagy and discuss their mechanisms, physiological roles, and possible links to human diseases.
Topics: Animals; Autophagosomes; Autophagy; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 31932525
DOI: 10.2183/pjab.96.001 -
Autophagy Jan 2022Ion exchange between intracellular and extracellular spaces is the basic mechanism for controlling cell metabolism and signal transduction. This process is mediated by...
Ion exchange between intracellular and extracellular spaces is the basic mechanism for controlling cell metabolism and signal transduction. This process is mediated by ion channels and transporters on the plasma membrane, or intracellular membranes that surround various organelles, in response to environmental stimuli. Macroautophagy (hereafter referred to as autophagy) is one of the lysosomal-dependent degradation pathways that maintains homeostasis through the degradation and recycling of cellular components (e.g., dysfunctional proteins and damaged organelles). Although autophagy-related (ATG) proteins play a central role in regulating the formation of autophagy-related member structures (e.g., phagophores, autophagosomes, and autolysosomes), the autophagic process also involves changes in expression and function of ion channels and transporters. Here we discuss current knowledge of the mechanisms that regulate autophagy in mammalian cells, with special attention to the ion channels and transporters. We also highlight prospects for the development of drugs targeting ion channels and transporters in autophagy.
Topics: Animals; Autophagosomes; Autophagy; Intracellular Membranes; Ion Channels; Lysosomes; Mammals
PubMed: 33657975
DOI: 10.1080/15548627.2021.1885147 -
Cells Mar 2020Autophagy is a catabolic process involving vacuolar sequestration of intracellular components and their targeting to lysosomes for degradation, thus supporting nutrient... (Review)
Review
Autophagy is a catabolic process involving vacuolar sequestration of intracellular components and their targeting to lysosomes for degradation, thus supporting nutrient recycling and energy regeneration. Accumulating evidence indicates that in addition to being a bulk, nonselective degradation mechanism, autophagy may selectively eliminate damaged mitochondria to promote mitochondrial turnover, a process termed "mitophagy". Mitophagy sequesters dysfunctional mitochondria via ubiquitination and cargo receptor recognition and has emerged as an important event in the regulation of liver physiology. Recent studies have shown that mitophagy may participate in the pathogenesis of various liver diseases, such as liver injury, liver steatosis/fatty liver disease, hepatocellular carcinoma, viral hepatitis, and hepatic fibrosis. This review summarizes the current knowledge on the molecular regulations and functions of mitophagy in liver physiology and the roles of mitophagy in the development of liver-related diseases. Furthermore, the therapeutic implications of targeting hepatic mitophagy to design a new strategy to cure liver diseases are discussed.
Topics: Autophagosomes; Autophagy; Humans; Liver; Liver Diseases; Mitophagy; Translational Research, Biomedical
PubMed: 32235615
DOI: 10.3390/cells9040831 -
Journal of Molecular and Cellular... Apr 2022Autophagy mediates cellular quality control mechanisms and energy homeostasis through lysosomal degradation. Autophagy is typically viewed as an adaptive process that... (Review)
Review
Autophagy mediates cellular quality control mechanisms and energy homeostasis through lysosomal degradation. Autophagy is typically viewed as an adaptive process that allows cells to survive against stress, such as nutrient deprivation and hypoxia. However, autophagy also mediates cell death during development and in response to stress. Cell death accompanied by autophagy activation and accumulation of autophagosomes has been classified as type II programmed cell death. Compared to the wealth of knowledge regarding the adaptive role of autophagy, however, the molecular mechanisms through which autophagy induces cell death and its functional significance are poorly understood. Autophagy is activated excessively under some conditions, causing uncontrolled degradation of cellular materials and cell death. An imbalance between autophagosome formation and lysosomal degradation causes a massive accumulation of autophagosomes, which subsequently causes cellular dysfunction and death. Dysregulation of autophagy induces a unique form of cell death, termed autosis, with defined morphological and biochemical features distinct from other forms of programmed cell death, such as apoptosis and necrosis. In the heart, dysregulated autophagy induces death of cardiomyocytes and actively mediates cardiac injury and dysfunction in some conditions, including reperfusion injury, doxorubicin cardiomyopathy, and lysosomal storage disorders. The goal in this review is to introduce the concept of autophagic cell death and discuss its functional significance in various cardiac conditions.
Topics: Apoptosis; Autophagosomes; Autophagy; Lysosomes; Myocytes, Cardiac
PubMed: 34919896
DOI: 10.1016/j.yjmcc.2021.12.006 -
Nature Communications Nov 2023Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body...
Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body plays pivotal roles during autophagosome formation, however, the underlying mechanisms are still not fully understood. Here we describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation. Mass spectrometry-based proteomics reveals significant enrichment of vesicle trafficking components within p62 body. Combining cellular experiments and biochemical reconstitution assays, we confirm the gathering of ATG9 and ATG16L1-positive vesicles around p62 body, especially in Atg2ab DKO cells with blocked lipid transfer and vesicle fusion. Interestingly, p62 body also regulates ATG9 and ATG16L vesicle trafficking flux intracellularly. We further determine the lipid contents associated with p62 body via lipidomic profiling. Moreover, with in vitro kinase assay, we uncover the functions of p62 body as a platform to assemble ULK1 complex and invigorate PI3KC3-C1 kinase cascade for PI3P generation. Collectively, our study raises a membrane-based working model for multifaceted p62 body in controlling autophagosome biogenesis, and highlights the interplay between membraneless condensates and membrane vesicles in regulating cellular functions.
Topics: Autophagosomes; Autophagy; Macroautophagy; Phagosomes; Autophagy-Related Proteins; Lipids
PubMed: 37957156
DOI: 10.1038/s41467-023-42829-8 -
Developmental Cell Aug 2021How autophagy initiation is regulated and what the functional significance of this regulation is are unknown. Here, we characterized the role of yeast Vac8 in autophagy...
How autophagy initiation is regulated and what the functional significance of this regulation is are unknown. Here, we characterized the role of yeast Vac8 in autophagy initiation through recruitment of PIK3C3-C1 to the phagophore assembly site (PAS). This recruitment is dependent on the palmitoylation of Vac8 and on its middle ARM domains for binding PIK3C3-C1. Vac8-mediated anchoring of PIK3C3-C1 promotes PtdIns3P generation at the PAS and recruitment of the PtdIns3P binding protein Atg18-Atg2. The mouse homolog of Vac8, ARMC3, is conserved and functions in autophagy in mouse testes. Mice lacking ARMC3 have normal viability but show complete male infertility. Proteomic analysis indicated that the autophagic degradation of cytosolic ribosomes was blocked in ARMC3-deficient spermatids, which caused low energy levels of mitochondria and motionless flagella. These studies uncovered a function of Vac8/ARMC3 in PtdIns3-kinase anchoring at the PAS and its physical significance in mammalian spermatogenesis with a germ tissue-specific autophagic function.
Topics: Adult; Animals; Autophagosomes; Autophagy; Cells, Cultured; Class III Phosphatidylinositol 3-Kinases; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Ribosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Sperm Motility; Sperm Tail; Spermatogenesis; Vesicular Transport Proteins
PubMed: 34428398
DOI: 10.1016/j.devcel.2021.07.015 -
Current Opinion in Cell Biology Aug 2021The de novo generation of double-membrane autophagosomes is the hallmark of autophagy. The initial membranous precursor cisterna, the phagophore, is very likely... (Review)
Review
The de novo generation of double-membrane autophagosomes is the hallmark of autophagy. The initial membranous precursor cisterna, the phagophore, is very likely generated by the fusion of vesicles and acts as a membrane seed for the subsequent expansion into an autophagosome. This latter step requires a massive convoy of lipids into the phagophore. In this review, we present recent advances in our understanding of the intracellular membrane sources and lipid delivery mechanisms, which principally rely on vesicular transport and membrane contact sites that contribute to autophagosome biogenesis. In this context, we discuss lipid biosynthesis and lipid remodeling events that play a crucial role in both phagophore nucleation and expansion.
Topics: Autophagosomes; Autophagy; Intracellular Membranes
PubMed: 33930785
DOI: 10.1016/j.ceb.2021.02.001 -
Current Biology : CB Dec 2022Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for the degradation of such cargo... (Review)
Review
Cellular homeostasis requires the swift and specific removal of damaged material. Selective autophagy represents a major pathway for the degradation of such cargo material. This is achieved by the sequestration of the cargo within double-membrane vesicles termed autophagosomes, which form de novo around the cargo and subsequently deliver their content to lysosomes for degradation. The importance of selective autophagy is exemplified by the various neurodegenerative diseases associated with defects in this pathway, including Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. It has become evident that cargo receptors are acting as Swiss army knives in selective autophagy by recognizing the cargo, orchestrating the recruitment of the machinery for autophagosome biogenesis, and closely aligning the membrane with the cargo. Furthermore, cargo receptors sequester ubiquitinated proteins into larger condensates upstream of autophagy induction. Here, we review recent insights into the mechanisms of action of cargo receptors in selective autophagy by focusing on the roles of sequestosome-like cargo receptors in the degradation of misfolded, ubiquitinated proteins and damaged mitochondria. We also highlight at which steps defects in their function result in the accumulation of harmful material and how this knowledge may guide the design of future therapies.
Topics: Ubiquitinated Proteins; Macroautophagy; Autophagy; Autophagosomes; Carrier Proteins
PubMed: 36538890
DOI: 10.1016/j.cub.2022.11.002 -
Journal of Molecular Biology Jan 2020Cells are constantly challenged by endogenous and exogenous stress sources. To cope with them, organisms have developed a series of defensive mechanisms to prevent and... (Review)
Review
Cells are constantly challenged by endogenous and exogenous stress sources. To cope with them, organisms have developed a series of defensive mechanisms to prevent and intercept the threats and to repair the generated damage. Autophagy, once defined as a waste-disposal or non-specific degradative pathway, has arisen as a new organizer of the different physiological stress responses. In the present review, we will discuss how autophagy is capable of orchestrate these pathways by the specific degradation of individual autophagosomal LC3/GABARAP-binding proteins, rather than the bulk degradation of harmful products or organelles.
Topics: Animals; Antiviral Restriction Factors; Autophagosomes; Autophagy; Circadian Rhythm; Cryptochromes; Humans; Macroautophagy; Nuclear Receptor Co-Repressor 1; Proteolysis; Sequestosome-1 Protein; Stress, Physiological; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 31220458
DOI: 10.1016/j.jmb.2019.06.013 -
The Journal of Biological Chemistry Nov 2023The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral...
The cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 kDa (TDP-43) has been linked to the progression of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 secreted into the extracellular space has been suggested to contribute to the cell-to-cell spread of the cytoplasmic accumulation of TDP-43 throughout the brain; however, the underlying mechanisms remain unknown. We herein demonstrated that the secretion of TDP-43 was stimulated by the inhibition of the autophagy-lysosomal pathway driven by progranulin (PGRN), a causal protein of frontotemporal lobar degeneration. Among modulators of autophagy, only vacuolar-ATPase inhibitors, such as bafilomycin A1 (Baf), increased the levels of the full-length and cleaved forms of TDP-43 and the autophagosome marker LC3-II (microtubule-associated proteins 1A/1B light chain 3B) in extracellular vesicle fractions prepared from the culture media of HeLa, SH-SY5Y, or NSC-34 cells, whereas vacuolin-1, MG132, chloroquine, rapamycin, and serum starvation did not. The C-terminal fragment of TDP-43 was required for Baf-induced TDP-43 secretion. The Baf treatment induced the translocation of the aggregate-prone GFP-tagged C-terminal fragment of TDP-43 and mCherry-tagged LC3 to the plasma membrane. The Baf-induced secretion of TDP-43 was attenuated in autophagy-deficient ATG16L1 knockout HeLa cells. The knockdown of PGRN induced the secretion of cleaved TDP-43 in an autophagy-dependent manner in HeLa cells. The KO of PGRN in mouse embryonic fibroblasts increased the secretion of the cleaved forms of TDP-43 and LC3-II. The treatment inducing TDP-43 secretion increased the nuclear translocation of GFP-tagged transcription factor EB, a master regulator of the autophagy-lysosomal pathway in SH-SY5Y cells. These results suggest that the secretion of TDP-43 is promoted by dysregulation of the PGRN-driven autophagy-lysosomal pathway.
Topics: Humans; Autophagy; DNA-Binding Proteins; HeLa Cells; Intercellular Signaling Peptides and Proteins; Lysosomes; Progranulins; Microtubule-Associated Proteins; Gene Expression Regulation; Extracellular Vesicles; Enzyme Inhibitors; Autophagosomes; Autophagy-Related Proteins
PubMed: 37739033
DOI: 10.1016/j.jbc.2023.105272