-
Advances in Experimental Medicine and... 2021Autophagy is a general term for the process of the lysosomal degradation of intracellular components, a process occurring exclusively in eukaryotic cells. Based on the...
Autophagy is a general term for the process of the lysosomal degradation of intracellular components, a process occurring exclusively in eukaryotic cells. Based on the way that intracellular substrates are transported to lysosomes, autophagy in mammalian cells can be divided into three main types: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Each type has its unique molecular machinery and is tightly regulated by various cellular signals, helping cells adapt to a changing environment. Autophagy can also be divided into two categories based on cargo selectivity: selective autophagy and nonselective autophagy. Nonselective autophagy refers to the bulk transport of organelles or other cytoplasmic components to lysosomes, while selective autophagy refers to the degradation of a specific substrate. Autophagy plays an essential role in maintaining cellular homeostasis, and dysregulation of it may participate in the pathological process of many human diseases.
Topics: Animals; Autophagy; Biological Transport; Homeostasis; Humans; Lysosomes; Signal Transduction
PubMed: 34260018
DOI: 10.1007/978-981-16-2830-6_1 -
PLoS Genetics Mar 2020
Topics: AMP-Activated Protein Kinases; Endosomal Sorting Complexes Required for Transport; Glucose; Lysosomes; Microautophagy; Proteasome Endopeptidase Complex
PubMed: 32191700
DOI: 10.1371/journal.pgen.1008631 -
Expert Review of Proteomics 2020Autophagy is an evolutionarily conserved cellular clearance process, by which cytosolic components are delivered to autolysosomes for breakdown and recycling to maintain... (Review)
Review
INTRODUCTION
Autophagy is an evolutionarily conserved cellular clearance process, by which cytosolic components are delivered to autolysosomes for breakdown and recycling to maintain cellular homeostasis. During the past decades, autophagy has been found to be tightly implicated in various physiological and pathological progresses. Unraveling the regulatory mechanisms of the autophagy process will contribute to the development of emerging autophagy-targeting strategies for the treatment of various diseases. Recently, the rapid development of proteomics approaches has enabled the use of large-scale unbiased strategies to unravel autophagy machinery.
AREAS COVERED
In this review, we will highlight the recent contributions of proteomics strategies in clarifying the autophagy machinery, with an emphasis on the three different types of autophagy (namely macroautophagy, microautophagy, and chaperone-mediated autophagy). We will also discuss the emerging role of proteomics approaches in investigating the mechanism of the autophagy-based unconventional secretory pathway (secretory autophagy).
EXPERT OPINION
Proteomics has provided an effective strategy for the comprehensive analysis of the autophagy process, which will broaden our understanding of autophagy machinery, and holds great promise for developing clinical therapies targeting autophagy.
Topics: Autophagy; Chaperone-Mediated Autophagy; Homeostasis; Humans; Lysosomes; Macroautophagy; Microautophagy; Proteome; Proteomics
PubMed: 32772586
DOI: 10.1080/14789450.2020.1808464 -
FEBS Letters Jan 2024The discovery of microautophagy, the direct engulfment of cytoplasmic material by the lysosome, dates back to 1966 in a morphological study of mammalian cells by... (Review)
Review
The discovery of microautophagy, the direct engulfment of cytoplasmic material by the lysosome, dates back to 1966 in a morphological study of mammalian cells by Christian de Duve. Since then, studies on microautophagy have shifted toward the elucidation of the physiological significance of the process. However, in contrast to macroautophagy, studies on the molecular mechanisms of microautophagy have been limited. Only recent studies revealed that ATG proteins involved in macroautophagy are also operative in several types of microautophagy and that ESCRT proteins, responsible for the multivesicular body pathway, play a central role in most microautophagy processes. In this review, we summarize our current knowledge on the function of ATG and ESCRT proteins in microautophagy.
Topics: Animals; Microautophagy; Autophagy; Lysosomes; Cytosol; Endosomal Sorting Complexes Required for Transport; Mammals
PubMed: 37857501
DOI: 10.1002/1873-3468.14760 -
BioRxiv : the Preprint Server For... Aug 2023The Ccr4-Not complex containing the Not4 ubiquitin ligase regulates gene transcription and mRNA decay, yet it also has poorly defined roles in translation, proteostasis,...
The Ccr4-Not complex containing the Not4 ubiquitin ligase regulates gene transcription and mRNA decay, yet it also has poorly defined roles in translation, proteostasis, and endolysosomal-dependent nutrient signaling. To define how Ccr4-Not mediated ubiquitin signaling regulates these additional processes, we performed quantitative proteomics in the yeast lacking the Not4 ubiquitin ligase, and also in cells overexpressing either wild-type or functionally inactive ligase. Herein, we provide evidence that both increased and decreased Ccr4-Not ubiquitin signaling disrupts ribosomal protein (RP) homeostasis independently of reduced RP mRNA changes or reductions in known Not4 ribosomal substrates. Surprisingly, we also find that both Not4-mediated ubiquitin signaling, and the Ccr4 subunit, actively inhibit 40S ribosomal autophagy. This 40S autophagy is independent of canonical Atg7-dependent macroautophagy, thus indicating microautophagy activation is responsible. Furthermore, the Not4 ligase genetically interacts with endolysosomal pathway effectors to control both RP expression and 40S autophagy efficiency. Overall, we demonstrate that balanced Ccr4-Not ligase activity maintains RP homeostasis, and that Ccr4-Not ubiquitin signaling interacts with the endolysosomal pathway to both regulate RP expression and inhibit 40S ribosomal autophagy.
PubMed: 37693548
DOI: 10.1101/2023.08.28.555095 -
Cells Jun 2022Autophagy is a pleiotropic and evolutionarily conserved process in eukaryotes that encompasses different types of mechanisms by which cells deliver cytoplasmic... (Review)
Review
Autophagy is a pleiotropic and evolutionarily conserved process in eukaryotes that encompasses different types of mechanisms by which cells deliver cytoplasmic constituents to the lysosome for degradation. Interestingly, in mammals, two different and specialized autophagic pathways, (i) the chaperone-mediated autophagy (CMA) and (ii) the endosomal microautophagy (eMI), both rely on the use of the same cytosolic chaperone HSPA8 (also known as HSC70) for targeting specific substrates to the lysosome. However, this is not true for all organisms, and differences exist between species with respect to the coexistence of these two autophagic routes. In this paper, we present an in-depth analysis of the evolutionary history of the main components of CMA and eMI and discuss how the observed discrepancies between species may contribute to improving our knowledge of these two functions and their interplays.
Topics: Animals; Autophagy; Chaperone-Mediated Autophagy; Lysosomes; Macroautophagy; Mammals; Microautophagy
PubMed: 35741074
DOI: 10.3390/cells11121945 -
Frontiers in Cell and Developmental... 2022Neuronal ceroid lipofuscinosis (NCL) is a collection of genetically inherited neurological disorders characterized by vision loss, seizure, brain death, and premature... (Review)
Review
Neuronal ceroid lipofuscinosis (NCL) is a collection of genetically inherited neurological disorders characterized by vision loss, seizure, brain death, and premature lethality. At the cellular level, a key pathologic hallmark of NCL is the build-up of autofluorescent storage materials (AFSM) in lysosomes of both neurons and non-neuronal cells. Molecular dissection of the genetic lesions underlying NCLs has shed significant insights into how disruption of lysosomal homeostasis may lead to lipofuscin accumulation and NCLs. Intriguingly, recent studies on DNAJC5/CSPα, a membrane associated HSC70 co-chaperone, have unexpectedly linked lipofuscin accumulation to two intimately coupled protein quality control processes at endolysosomes. This review discusses how deregulation of unconventional protein secretion and endosomal microautophagy (eMI) contributes to lipofuscin accumulation and neurodegeneration.
PubMed: 35620055
DOI: 10.3389/fcell.2022.906453 -
ELife Apr 2023The ubiquitin-binding NBR1 autophagy receptor plays a prominent role in recognizing ubiquitylated protein aggregates for vacuolar degradation by macroautophagy. Here, we...
The ubiquitin-binding NBR1 autophagy receptor plays a prominent role in recognizing ubiquitylated protein aggregates for vacuolar degradation by macroautophagy. Here, we show that upon exposing plants to intense light, NBR1 associates with photodamaged chloroplasts independently of ATG7, a core component of the canonical autophagy machinery. NBR1 coats both the surface and interior of chloroplasts, which is then followed by direct engulfment of the organelles into the central vacuole via a microautophagy-type process. The relocalization of NBR1 into chloroplasts does not require the chloroplast translocon complexes embedded in the envelope but is instead greatly enhanced by removing the self-oligomerization mPB1 domain of NBR1. The delivery of NBR1-decorated chloroplasts into vacuoles depends on the ubiquitin-binding UBA2 domain of NBR1 but is independent of the ubiquitin E3 ligases SP1 and PUB4, known to direct the ubiquitylation of chloroplast surface proteins. Compared to wild-type plants, mutants have altered levels of a subset of chloroplast proteins and display abnormal chloroplast density and sizes upon high light exposure. We postulate that, as photodamaged chloroplasts lose envelope integrity, cytosolic ligases reach the chloroplast interior to ubiquitylate thylakoid and stroma proteins which are then recognized by NBR1 for autophagic clearance. This study uncovers a new function of NBR1 in the degradation of damaged chloroplasts by microautophagy.
Topics: Autophagy; Carrier Proteins; Arabidopsis; Ubiquitin; Membrane Proteins; Chloroplasts; Ubiquitin-Protein Ligases; Arabidopsis Proteins
PubMed: 37070813
DOI: 10.7554/eLife.86030 -
Autophagy May 2024LC3 lipidation plays an important role in the regulation of macroautophagy and LC3-associated microautophagy. The E1-like enzyme ATG7 is one of the core components that...
LC3 lipidation plays an important role in the regulation of macroautophagy and LC3-associated microautophagy. The E1-like enzyme ATG7 is one of the core components that are directly involved in LC3 lipidation reaction. Here, we provide evidence showing that acetylation of ATG7 tightly controls its enzyme activity to regulate the induction of macroautophagy and LC3-associated microautophagy. Mechanistically, acetylation of ATG7 disrupts its interaction with the E2-like enzyme ATG3, leading to an inhibition of LC3 lipidation and . Functionally, in response to various different stimuli, cellular ATG7 undergoes deacetylation to induce macroautophagy and LC3-associated microautophagy, which are necessary for cells to eliminate cytoplasmic DNA and degrade lysosome membrane proteins, respectively. Taken together, these findings reveal that ATG7 acetylation acts as a critical rheostat in controlling LC3 lipidation and related cellular processes. AMPK: AMP-activated protein kinase; ATG: autophagy-related; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; CREBBP/CBP: CREB binding protein; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EP300/p300: E1A binding protein p300; IFNB1: interferon beta 1; ISD: interferon stimulatory DNA; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; NAM: nicotinamide; PE: phosphatidylethanolamine; PTM: post-translational modification; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SIRT: sirtuin; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TSA: trichostatin A; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2; WT: wild-type.
Topics: Animals; Humans; Mice; Acetylation; Autophagy; Autophagy-Related Protein 7; Autophagy-Related Proteins; Lysosomes; Macroautophagy; Microtubule-Associated Proteins; Ubiquitin-Conjugating Enzymes
PubMed: 37999993
DOI: 10.1080/15548627.2023.2287932 -
Frontiers in Molecular Neuroscience 2023Autophagy is a conserved physiological intracellular mechanism responsible for the degradation and recycling of cytoplasmic constituents (e.g., damaged organelles, and... (Review)
Review
BACKGROUND
Autophagy is a conserved physiological intracellular mechanism responsible for the degradation and recycling of cytoplasmic constituents (e.g., damaged organelles, and protein aggregates) to maintain cell homeostasis. Aberrant autophagy has been observed in neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD), and recently aberrant autophagy has been associated with mood disorders, such as depression. Several methods have been developed to study the complex and tightly regulated mechanisms of autophagy. methods applied to autophagy research are used to identify molecular key players involved in dysfunctional autophagy and to screen autophagy regulators with therapeutic applications in neurological diseases and mood disorders. Therefore, the aims of this narrative review are (1) to compile information on the cell-based methods used in autophagy research, (2) to discuss their application, and (3) to create a catalog of traditional and novel methods applied in neurodegenerative diseases and depression.
METHODS
Pubmed and Google Scholar were used to retrieve relevant studies on autophagy mechanisms in neurological diseases and depression using a combination of search terms per mechanism and disease (e.g., "macroautophagy" and "Alzheimer's disease"). A total of 37 studies were included (14 in PD, 8 in AD, 5 in ALS, 5 in %, and 5 in depression).
RESULTS
A repertoire of traditional and novel approaches and techniques was compiled and discussed. The methods used in autophagy research focused on the mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy. The tools presented in this review can be applied to explore pathophysiological mechanisms at a molecular level and to screen for potential therapeutic agents and their mechanism of action, which can be of great importance to understanding disease biology and potential therapeutic options in the context of neurodegenerative disorders and depression.
CONCLUSION
This is the first review to compile, discuss, and provide a catalog of traditional and novel models applied to neurodegenerative disorders and depression.
PubMed: 37122628
DOI: 10.3389/fnmol.2023.1168948