-
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 -
Journal of Pharmacological Sciences Jul 2023Missense mutations of ubiquilin 2 (UBQLN2) have been identified to cause X-linked amyotrophic lateral sclerosis (ALS). Proteasome-mediated protein degradation is...
Missense mutations of ubiquilin 2 (UBQLN2) have been identified to cause X-linked amyotrophic lateral sclerosis (ALS). Proteasome-mediated protein degradation is reported to be impaired by ALS-associated mutations of UBQLN2. However, it remains unknown how these mutations affect autophagy-lysosome protein degradation, which consists of macroautophagy (MA), microautophagy (mA), and chaperone-mediated autophagy (CMA). Using a CMA/mA fluorescence reporter we found that overexpression of wild-type UBQLN2 impairs CMA. Conversely, knockdown of endogenous UBQLN2 increases CMA activity, suggesting that normally UBQLN2 negatively regulates CMA. ALS-associated mutant forms of UBQLN2 exacerbate this impairment of CMA. Using cells stably transfected with wild-type or ALS-associated mutant UBQLN2, we further determined that wild-type UBQLN2 increased the ratio of LAMP2A (a CMA-related protein) to LAMP1 (a lysosomal protein). This could represent a compensatory reaction to the impairment of CMA by wild-type UBQLN2. However, ALS-associated mutant UBQLN2 failed to show this compensation, exacerbating the impairment of CMA by mutant UBQLN2. We further demonstrated that ALS-associated mutant forms of UBQLN2 also impair MA, but wild-type UBQLN2 does not. These results support the view that ALS-associated mutant forms of UBQLN2 impair both CMA and MA which may contribute to the neurodegeneration observed in patients with UBQLN2-mediated ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Adaptor Proteins, Signal Transducing; Autophagy; Mutation; Autophagy-Related Proteins; Transcription Factors; Lysosomes
PubMed: 37257946
DOI: 10.1016/j.jphs.2023.05.002 -
Oxidative Medicine and Cellular... 2023Autophagy is a dynamic process that regulates the selective and nonselective degradation of cytoplasmic components, such as damaged organelles and protein aggregates... (Review)
Review
Autophagy is a dynamic process that regulates the selective and nonselective degradation of cytoplasmic components, such as damaged organelles and protein aggregates inside lysosomes to maintain tissue homeostasis. Different types of autophagy including macroautophagy, microautophagy, and chaperon-mediated autophagy (CMA) have been implicated in a variety of pathological conditions, such as cancer, aging, neurodegeneration, and developmental disorders. Furthermore, the molecular mechanism and biological functions of autophagy have been extensively studied in vertebrate hematopoiesis and human blood malignancies. In recent years, the hematopoietic lineage-specific roles of different autophagy-related () genes have gained more attention. The evolution of gene-editing technology and the easy access nature of hematopoietic stem cells (HSCs), hematopoietic progenitors, and precursor cells have facilitated the autophagy research to better understand how genes function in the hematopoietic system. Taking advantage of the gene-editing platform, this review has summarized the roles of different s at the hematopoietic cell level, their dysregulation, and pathological consequences throughout hematopoiesis.
Topics: Humans; Autophagy; Neoplasms; Organelles; Lysosomes; Aging
PubMed: 37180758
DOI: 10.1155/2023/8257217 -
Cells May 2023Physiologically, autophagy is an evolutionarily conserved and self-degradative process in cells. Autophagy carries out normal physiological roles throughout mammalian... (Review)
Review
Physiologically, autophagy is an evolutionarily conserved and self-degradative process in cells. Autophagy carries out normal physiological roles throughout mammalian life. Accumulating evidence shows autophagy as a mechanism for cellular growth, development, differentiation, survival, and homeostasis. In male reproductive systems, normal spermatogenesis and steroidogenesis need a balance between degradation and energy supply to preserve cellular metabolic homeostasis. The main process of autophagy includes the formation and maturation of the phagophore, autophagosome, and autolysosome. Autophagy is controlled by a group of autophagy-related genes that form the core machinery of autophagy. Three types of autophagy mechanisms have been discovered in mammalian cells: macroautophagy, microautophagy, and chaperone-mediated autophagy. Autophagy is classified as non-selective or selective. Non-selective macroautophagy randomly engulfs the cytoplasmic components in autophagosomes that are degraded by lysosomal enzymes. While selective macroautophagy precisely identifies and degrades a specific element, current findings have shown the novel functional roles of autophagy in male reproduction. It has been recognized that dysfunction in the autophagy process can be associated with male infertility. Overall, this review provides an overview of the cellular and molecular basics of autophagy and summarizes the latest findings on the key role of autophagy in mammalian male reproductive physiology.
Topics: Animals; Male; Macroautophagy; Autophagy; Autophagosomes; Microautophagy; Lysosomes; Mammals
PubMed: 37174722
DOI: 10.3390/cells12091322 -
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 -
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 -
Nutricion Hospitalaria Apr 2023Autophagy is a very active process that plays an important role in cell and organ differentiation and remodelling, being a crucial system to guarantee health. This...
Autophagy is a very active process that plays an important role in cell and organ differentiation and remodelling, being a crucial system to guarantee health. This physiological process is activated in starvation and inhibited in the presence of nutrients. This short review comments on the three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy, as well as different aspects that control autophagy and its relationship with health and degenerative diseases. As autophagy is highly dependent on functional autophagy (ATG) proteins integrating the phagophore, the role of some key ATG genes and epigenes are briefly commented on. The manuscript deepens discussing some central aspects of type-2 diabetes mellitus and their relationship with the cell cleaning process and mitochondria homeostasis maintenance, as well as the mechanisms through which antidiabetic drugs affect autophagy. Well-designed studies are needed to elucidate whether autophagy plays a casual or causal role in T2DM.
Topics: Humans; Autophagy; Homeostasis; Mitochondria; Diabetes Mellitus, Type 2
PubMed: 36927007
DOI: 10.20960/nh.04555 -
Nature Cell Biology Mar 2023Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING...
Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs.
Topics: Animals; Humans; Adenosine Triphosphatases; Endosomal Sorting Complexes Required for Transport; Endosomes; Interferon Type I; Microautophagy; Protein Transport; Signal Transduction; Membrane Proteins
PubMed: 36918692
DOI: 10.1038/s41556-023-01098-9 -
Nature Cell Biology Mar 2023
Topics: Microautophagy; Animals; Membrane Proteins; Endosomal Sorting Complexes Required for Transport
PubMed: 36918691
DOI: 10.1038/s41556-022-01084-7 -
Autophagy May 2023Light is essential for plant growth, but excessive light energy produces reactive oxygen species (ROS), which can seriously damage cells. Mutants defective in...
Light is essential for plant growth, but excessive light energy produces reactive oxygen species (ROS), which can seriously damage cells. Mutants defective in (autophagy related) genes show light intensity-dependent leaf damage and ROS accumulation. We found that autophagy is one of the crucial systems in protecting plants from ROS-induced damage by removing oxidative peroxisomes. Damaged peroxisomes are targeted by the PtdIns3P marker and specifically engulfed by phagophores labeled by ATG18a-GFP. Under high-intensity light, huge peroxisome aggregates are induced and captured by vacuolar membranes. Research provides a deeper understanding of plant stress response to light irradiation.
Topics: Macroautophagy; Autophagy; Reactive Oxygen Species; Oxidative Stress; Plants; Peroxisomes
PubMed: 36760098
DOI: 10.1080/15548627.2023.2175570