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Neuron Mar 2022The term autophagy encompasses different pathways that route cytoplasmic material to lysosomes for degradation and includes macroautophagy, chaperone-mediated autophagy,... (Review)
Review
The term autophagy encompasses different pathways that route cytoplasmic material to lysosomes for degradation and includes macroautophagy, chaperone-mediated autophagy, and microautophagy. Since these pathways are crucial for degradation of aggregate-prone proteins and dysfunctional organelles such as mitochondria, they help to maintain cellular homeostasis. As post-mitotic neurons cannot dilute unwanted protein and organelle accumulation by cell division, the nervous system is particularly dependent on autophagic pathways. This dependence may be a vulnerability as people age and these processes become less effective in the brain. Here, we will review how the different autophagic pathways may protect against neurodegeneration, giving examples of both polygenic and monogenic diseases. We have considered how autophagy may have roles in normal CNS functions and the relationships between these degradative pathways and different types of programmed cell death. Finally, we will provide an overview of recently described strategies for upregulating autophagic pathways for therapeutic purposes.
Topics: Apoptosis; Autophagy; Brain; Humans; Lysosomes; Neurons
PubMed: 35134347
DOI: 10.1016/j.neuron.2022.01.017 -
Nature Reviews. Molecular Cell Biology Mar 2023'Autophagy' refers to an evolutionarily conserved process through which cellular contents, such as damaged organelles and protein aggregates, are delivered to lysosomes... (Review)
Review
'Autophagy' refers to an evolutionarily conserved process through which cellular contents, such as damaged organelles and protein aggregates, are delivered to lysosomes for degradation. Different forms of autophagy have been described on the basis of the nature of the cargoes and the means used to deliver them to lysosomes. At present, the prevailing categories of autophagy in mammalian cells are macroautophagy, microautophagy and chaperone-mediated autophagy. The molecular mechanisms and biological functions of macroautophagy and chaperone-mediated autophagy have been extensively studied, but microautophagy has received much less attention. In recent years, there has been a growth in research on microautophagy, first in yeast and then in mammalian cells. Here we review this form of autophagy, focusing on selective forms of microautophagy. We also discuss the upstream regulatory mechanisms, the crosstalk between macroautophagy and microautophagy, and the functional implications of microautophagy in diseases such as cancer and neurodegenerative disorders in humans. Future research into microautophagy will provide opportunities to develop novel interventional strategies for autophagy- and lysosome-related diseases.
Topics: Animals; Humans; Microautophagy; Autophagy; Lysosomes; Cell Communication; Macroautophagy; Mammals
PubMed: 36097284
DOI: 10.1038/s41580-022-00529-z -
Nature Reviews. Genetics Jun 2023Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic... (Review)
Review
Macroautophagy and microautophagy are highly conserved eukaryotic cellular processes that degrade cytoplasmic material in lysosomes. Both pathways involve characteristic membrane dynamics regulated by autophagy-related proteins and other molecules, some of which are shared between the two pathways. Over the past few years, the application of new technologies, such as cryo-electron microscopy, coevolution-based structural prediction and in vitro reconstitution, has revealed the functions of individual autophagy gene products, especially in autophagy induction, membrane reorganization and cargo recognition. Concomitantly, mutations in autophagy genes have been linked to human disorders, particularly neurodegenerative diseases, emphasizing the potential pathogenic implications of autophagy defects. Accumulating genome data have also illuminated the evolution of autophagy genes within eukaryotes as well as their transition from possible ancestral elements in prokaryotes.
Topics: Humans; Cryoelectron Microscopy; Autophagy; Lysosomes; Proteins; Eukaryota; Biology
PubMed: 36635405
DOI: 10.1038/s41576-022-00562-w -
Autophagy Jan 2022Autophagic pathways cross with lipid homeostasis and thus provide energy and essential building blocks that are indispensable for liver functions. Energy deficiencies... (Review)
Review
Autophagic pathways cross with lipid homeostasis and thus provide energy and essential building blocks that are indispensable for liver functions. Energy deficiencies are compensated by breaking down lipid droplets (LDs), intracellular organelles that store neutral lipids, in part by a selective type of autophagy, referred to as lipophagy. The process of lipophagy does not appear to be properly regulated in fatty liver diseases (FLDs), an important risk factor for the development of hepatocellular carcinomas (HCC). Here we provide an overview on our current knowledge of the biogenesis and functions of LDs, and the mechanisms underlying their lysosomal turnover by autophagic processes. This review also focuses on nonalcoholic steatohepatitis (NASH), a specific type of FLD characterized by steatosis, chronic inflammation and cell death. Particular attention is paid to the role of macroautophagy and macrolipophagy in relation to the parenchymal and non-parenchymal cells of the liver in NASH, as this disease has been associated with inappropriate lipophagy in various cell types of the liver.: ACAT: acetyl-CoA acetyltransferase; ACAC/ACC: acetyl-CoA carboxylase; AKT: AKT serine/threonine kinase; ATG: autophagy related; AUP1: AUP1 lipid droplet regulating VLDL assembly factor; BECN1/Vps30/Atg6: beclin 1; BSCL2/seipin: BSCL2 lipid droplet biogenesis associated, seipin; CMA: chaperone-mediated autophagy; CREB1/CREB: cAMP responsive element binding protein 1; CXCR3: C-X-C motif chemokine receptor 3; DAGs: diacylglycerols; DAMPs: danger/damage-associated molecular patterns; DEN: diethylnitrosamine; DGAT: diacylglycerol O-acyltransferase; DNL: lipogenesis; EHBP1/NACSIN (EH domain binding protein 1); EHD2/PAST2: EH domain containing 2; CoA: coenzyme A; CCL/chemokines: chemokine ligands; CCl carbon tetrachloride; ER: endoplasmic reticulum; ESCRT: endosomal sorting complexes required for transport; FA: fatty acid; FFAs: free fatty acids; FFC: high saturated fats, fructose and cholesterol; FGF21: fibroblast growth factor 21; FITM/FIT: fat storage inducing transmembrane protein; FLD: fatty liver diseases; FOXO: forkhead box O; GABARAP: GABA type A receptor-associated protein; GPAT: glycerol-3-phosphate acyltransferase; HCC: hepatocellular carcinoma; HDAC6: histone deacetylase 6; HECT: homologous to E6-AP C-terminus; HFCD: high fat, choline deficient; HFD: high-fat diet; HSCs: hepatic stellate cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; ITCH/AIP4: itchy E3 ubiquitin protein ligase; KCs: Kupffer cells; LAMP2A: lysosomal associated membrane protein 2A; LDs: lipid droplets; LDL: low density lipoprotein; LEP/OB: leptin; LEPR/OBR: leptin receptor; LIPA/LAL: lipase A, lysosomal acid type; LIPE/HSL: lipase E, hormone sensitive type; LIR: LC3-interacting region; LPS: lipopolysaccharide; LSECs: liver sinusoidal endothelial cells; MAGs: monoacylglycerols; MAPK: mitogen-activated protein kinase; MAP3K5/ASK1: mitogen-activated protein kinase kinase kinase 5; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCD: methionine-choline deficient; MGLL/MGL: monoglyceride lipase; MLXIPL/ChREBP: MLX interacting protein like; MTORC1: mechanistic target of rapamycin kinase complex 1; NAFLD: nonalcoholic fatty liver disease; NAS: NAFLD activity score; NASH: nonalcoholic steatohepatitis; NPC: NPC intracellular cholesterol transporter; NR1H3/LXRα: nuclear receptor subfamily 1 group H member 3; NR1H4/FXR: nuclear receptor subfamily 1 group H member 4; PDGF: platelet derived growth factor; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PLIN: perilipin; PNPLA: patatin like phospholipase domain containing; PNPLA2/ATGL: patatin like phospholipase domain containing 2; PNPLA3/adiponutrin: patatin like phospholipase domain containing 3; PPAR: peroxisome proliferator activated receptor; PPARA/PPARα: peroxisome proliferator activated receptor alpha; PPARD/PPARδ: peroxisome proliferator activated receptor delta; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; PPARGC1A/PGC1α: PPARG coactivator 1 alpha; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; ROS: reactive oxygen species; SE: sterol esters; SIRT1: sirtuin 1; SPART/SPG20: spartin; SQSTM1/p62: sequestosome 1; SREBF1/SREBP1c: sterol regulatory element binding transcription factor 1; TAGs: triacylglycerols; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; TGFB1/TGFβ: transforming growth factor beta 1; Ub: ubiquitin; UBE2G2/UBC7: ubiquitin conjugating enzyme E2 G2; ULK1/Atg1: unc-51 like autophagy activating kinase 1; USF1: upstream transcription factor 1; VLDL: very-low density lipoprotein; VPS: vacuolar protein sorting; WIPI: WD-repeat domain, phosphoinositide interacting; WDR: WD repeat domain.
Topics: Autophagy; Carcinoma, Hepatocellular; Humans; Lipid Droplets; Liver Neoplasms; Non-alcoholic Fatty Liver Disease
PubMed: 33794741
DOI: 10.1080/15548627.2021.1895658 -
Trends in Cell Biology May 2020The endoplasmic reticulum (ER) is the largest organelle in cells and has fundamental functions, such as folding, processing, and trafficking of proteins, cellular... (Review)
Review
The endoplasmic reticulum (ER) is the largest organelle in cells and has fundamental functions, such as folding, processing, and trafficking of proteins, cellular metabolism, and ion storage. To maintain its function, it is turned over constitutively, and even more actively under certain stress conditions. Quality control of the ER is mediated primarily by two pathways: the ubiquitin-proteasome system and autophagy (termed 'ER-phagy'). The identification of ER-phagy adaptor molecules has shed light on the mechanisms and physiological significance of ER-phagy. Here, we describe recent findings on various types of ER-phagy and present unanswered questions related to their mechanism and regulation.
Topics: Animals; Autophagy; Endoplasmic Reticulum; Humans; Models, Biological; Proteasome Endopeptidase Complex; Protein Aggregates; Protein Folding; Ubiquitin
PubMed: 32302550
DOI: 10.1016/j.tcb.2020.02.001 -
Cellular and Molecular Life Sciences :... Dec 2021Lysosomes are single membrane-bound organelles containing acid hydrolases responsible for the degradation of cellular cargo and maintenance of cellular homeostasis.... (Review)
Review
Lysosomes are single membrane-bound organelles containing acid hydrolases responsible for the degradation of cellular cargo and maintenance of cellular homeostasis. Lysosomes could originate from pre-existing endolysosomes or autolysosomes, acting as a critical juncture between autophagy and endocytosis. Stress that triggers lysosomal membrane permeabilization can be altered by ESCRT complexes; however, irreparable damage to the membrane results in the induction of a selective lysosomal degradation pathway, specifically lysophagy. Lysosomes play an indispensable role in different types of autophagy, including microautophagy, macroautophagy, and chaperone-mediated autophagy, and various cell death pathways such as lysosomal cell death, apoptotic cell death, and autophagic cell death. In this review, we discuss lysosomal reformation, maintenance, and degradation pathways following the involvement of the lysosome in autophagy and cell death, which are related to several pathophysiological conditions observed in humans.
Topics: Aging; Animals; Apoptosis; Autophagy; Cell Membrane; Endocytosis; Humans; Intracellular Membranes; Lysosomes
PubMed: 34716768
DOI: 10.1007/s00018-021-03988-3 -
The EMBO Journal Jul 2017Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms.... (Review)
Review
Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.
Topics: Animals; Autophagy; Caenorhabditis elegans; Drosophila melanogaster; Gene Regulatory Networks; Mice; Saccharomyces cerevisiae; Terminology as Topic
PubMed: 28596378
DOI: 10.15252/embj.201796697 -
Journal of Nippon Medical School =... Mar 2024Autophagy is a self-digestive process that is conserved in eukaryotic cells and responsible for maintaining cellular homeostasis through proteolysis. By this process,... (Review)
Review
Autophagy is a self-digestive process that is conserved in eukaryotic cells and responsible for maintaining cellular homeostasis through proteolysis. By this process, cells break down their own components in lysosomes. Autophagy can be classified into three categories: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy involves membrane elongation and microautophagy involves membrane internalization, and both pathways undergo selective or non-selective processes that transport cytoplasmic components into lysosomes to be degraded. CMA, however, involves selective incorporation of cytosolic materials into lysosomes without membrane deformation. All three categories of autophagy have attracted much attention due to their involvement in various biological phenomena and their relevance to human diseases, such as neurodegenerative diseases and cancer. Clarification of the molecular mechanisms behind these processes is key to understanding autophagy and recent studies have made major progress in this regard, especially for the mechanisms of initiation and membrane elongation in macroautophagy and substrate recognition in microautophagy and CMA. Furthermore, it is becoming evident that the three categories of autophagy are related to each other despite their implementation by different sets of proteins and the involvement of completely different membrane dynamics. In this review, recent progress in macroautophagy, microautophagy, and CMA are summarized.
Topics: Humans; Microautophagy; Chaperone-Mediated Autophagy; Macroautophagy; Autophagy; Neurodegenerative Diseases
PubMed: 37271546
DOI: 10.1272/jnms.JNMS.2024_91-102 -
Autophagy Oct 2022The endolysosomal system not only is an integral part of the cellular catabolic machinery that processes and recycles nutrients for synthesis of biomaterials, but also...
The endolysosomal system not only is an integral part of the cellular catabolic machinery that processes and recycles nutrients for synthesis of biomaterials, but also acts as signaling hub to sense and coordinate the energy state of cells with growth and differentiation. Lysosomal dysfunction adversely influences vesicular transport-dependent macromolecular degradation and thus causes serious problems for human health. In mammalian cells, loss of the lysosome associated membrane proteins LAMP1 and LAMP2 strongly affects autophagy and cholesterol trafficking. Here we show that the previously uncharacterized Lamp1 is a ortholog of vertebrate LAMP1 and LAMP2. Surprisingly and in contrast to double-mutant mice, Lamp1 is not required for viability or autophagy, suggesting that fly and vertebrate LAMP proteins acquired distinct functions, or that autophagy defects in mutants may have indirect causes. However, Lamp1 deficiency results in an increase in the number of acidic organelles in flies. Furthermore, we find that mutant larvae have defects in lipid metabolism as they show elevated levels of sterols and diacylglycerols (DAGs). Because DAGs are the main lipid species used for transport through the hemolymph (blood) in insects, our results indicate broader functions of Lamp1 in lipid transport. Our findings make an ideal model to study the role of LAMP proteins in lipid assimilation without the confounding effects of their storage and without interfering with autophagic processes.: aa: amino acid; AL: autolysosome; AP: autophagosome; APGL: autophagolysosome; AV: autophagic vacuole (i.e. AP and APGL/AL); AVi: early/initial autophagic vacuoles; AVd: late/degradative autophagic vacuoles; : autophagy-related; CMA: chaperone-mediated autophagy; Cnx99A: Calnexin 99A; DAG: diacylglycerol; eMI: endosomal microautophagy; ESCRT: endosomal sorting complexes required for transport; FB: fat body; HDL: high-density lipoprotein; Hrs: Hepatocyte growth factor regulated tyrosine kinase substrate; LAMP: lysosomal associated membrane protein; LD: lipid droplet; LDL: low-density lipoprotein; Lpp: lipophorin; LTP: Lipid transfer particle; LTR: LysoTracker Red; MA: macroautophagy; MCC: Manders colocalization coefficient; MEF: mouse embryonic fibroblast MTORC: mechanistic target of rapamycin kinase complex; PV: parasitophorous vacuole; SNARE: soluble N-ethylmaleimide sensitive factor attachment protein receptor; Snap: Synaptosomal-associated protein; st: starved; TAG: triacylglycerol; TEM: transmission electron microscopy; TFEB/Mitf: transcription factor EB; TM: transmembrane domain; tub: tubulin; UTR: untranslated region.
Topics: Amino Acids; Animals; Autophagy; Biocompatible Materials; Calnexin; Diglycerides; Drosophila; Drosophila Proteins; Endosomal Sorting Complexes Required for Transport; Ethylmaleimide; Fibroblasts; Hepatocyte Growth Factor; Humans; Lipoproteins, HDL; Lipoproteins, LDL; Lysosomal Membrane Proteins; Lysosomes; Mammals; Mice; Protein-Tyrosine Kinases; SNARE Proteins; Sirolimus; Sterols; Triglycerides; Tubulin; Untranslated Regions
PubMed: 35266854
DOI: 10.1080/15548627.2022.2038999 -
Advances in Experimental Medicine and... 2019Protein homeostasis is essential for maintaining cell survival. Protein synthesis and degradation coordinately regulate protein homeostasis. Chaperone-mediated autophagy... (Review)
Review
Protein homeostasis is essential for maintaining cell survival. Protein synthesis and degradation coordinately regulate protein homeostasis. Chaperone-mediated autophagy (CMA) was the first lysosomal process to be discovered by which intracellular components are selectively degraded. This process involves the recognition of the substrate, the unfolding and translocation of the substrate, and the degradation of the substrate. By degrading specific target proteins in a timely manner, CMA is involved in a variety of cellular activities. In the past few years, we have acquired a better understanding of how CMA is regulated. It has been reported that peroxide accumulation, aging and/or other pathological signals interfere with CMA function, which in turn induces neurodegenerative diseases, cancer, and other diseases. Combining results from the current research, we summarize the basic processes, regulatory mechanisms, and physiological functions of CMA and discuss its critical role in the development of diseases.
Topics: Autophagy; Humans; Lysosomes; Molecular Chaperones; Neoplasms; Neurodegenerative Diseases
PubMed: 31776997
DOI: 10.1007/978-981-15-0602-4_20