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Current Opinion in Cell Biology Apr 2016Autophagy mediates the (non-)selective bulk degradation of cytoplasm, protein aggregates, damaged organelles and certain pathogens. The endosomal membrane system uses... (Review)
Review
Autophagy mediates the (non-)selective bulk degradation of cytoplasm, protein aggregates, damaged organelles and certain pathogens. The endosomal membrane system uses multivesicular bodies (MVBs) to selectively deliver ubiquitinated membrane proteins together with extracellular components into lysosomes. Microautophagy (MA) and chaperone-mediated autophagy (CMA) additionally contribute to the selective delivery of cargo into lysosomes. The coordinated function of these lysosomal degradation pathways is essential to maintain cellular homeostasis. Their activity is controlled by mTOR (mammalian target of rapamycin) signaling and thus coupled to metabolic processes during cell growth. Here, we will discuss how TORC1 on lysosomes and TORC2 at the plasma membrane coordinate the different membrane biogenesis pathways with cargo selection, vesicle transport and fusion with lysosomes in response to intracellular and extracellular cues.
Topics: Animals; Autophagy; Biological Transport; Endosomes; Humans; Lysosomes; Signal Transduction; Ubiquitin
PubMed: 26827287
DOI: 10.1016/j.ceb.2016.01.006 -
The Journal of Cell Biology Jan 2023At the trans-Golgi, complex traffic connections exist to the endolysosomal system additional to the main Golgi-to-plasma membrane secretory route. Here, we investigated...
At the trans-Golgi, complex traffic connections exist to the endolysosomal system additional to the main Golgi-to-plasma membrane secretory route. Here, we investigated three hits in a Drosophila screen displaying secretory cargo accumulation in autophagic vesicles: ESCRT-III component Vps20, SNARE-binding Rop, and lysosomal pump subunit VhaPPA1-1. We found that Vps20, Rop, and lysosomal markers localize near the trans-Golgi. Furthermore, we document that the vicinity of the trans-Golgi is the main cellular location for lysosomes and that early, late, and recycling endosomes associate as well with a trans-Golgi-associated degradative compartment where basal microautophagy of secretory cargo and other materials occurs. Disruption of this compartment causes cargo accumulation in our hits, including Munc18 homolog Rop, required with Syx1 and Syx4 for Rab11-mediated endosomal recycling. Finally, besides basal microautophagy, we show that the trans-Golgi-associated degradative compartment contributes to the growth of autophagic vesicles in developmental and starvation-induced macroautophagy. Our results argue that the fly trans-Golgi is the gravitational center of the whole endomembrane system.
Topics: Animals; Autophagy; Drosophila; Drosophila Proteins; Endosomal Sorting Complexes Required for Transport; Endosomes; Golgi Apparatus; Lysosomes; Nerve Tissue Proteins; Protein Transport; SNARE Proteins; rab GTP-Binding Proteins
PubMed: 36239631
DOI: 10.1083/jcb.202203045 -
Neuroscience Bulletin Mar 2024Autophagy involves the sequestration and delivery of cytoplasmic materials to lysosomes, where proteins, lipids, and organelles are degraded and recycled. According to... (Review)
Review
Autophagy involves the sequestration and delivery of cytoplasmic materials to lysosomes, where proteins, lipids, and organelles are degraded and recycled. According to the way the cytoplasmic components are engulfed, autophagy can be divided into macroautophagy, microautophagy, and chaperone-mediated autophagy. Recently, many studies have found that autophagy plays an important role in neurological diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, neuronal excitotoxicity, and cerebral ischemia. Autophagy maintains cell homeostasis in the nervous system via degradation of misfolded proteins, elimination of damaged organelles, and regulation of apoptosis and inflammation. AMPK-mTOR, Beclin 1, TP53, endoplasmic reticulum stress, and other signal pathways are involved in the regulation of autophagy and can be used as potential therapeutic targets for neurological diseases. Here, we discuss the role, functions, and signal pathways of autophagy in neurological diseases, which will shed light on the pathogenic mechanisms of neurological diseases and suggest novel targets for therapies.
Topics: Humans; Autophagy; Nervous System Diseases; Parkinson Disease; Alzheimer Disease; Huntington Disease
PubMed: 37856037
DOI: 10.1007/s12264-023-01120-y -
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 -
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 -
International Journal of General... 2022Proteostasis, also known as protein homeostasis, is critical for cell survival. Autophagy is a cellular process that degrades and recycles damaged or long-lived... (Review)
Review
Proteostasis, also known as protein homeostasis, is critical for cell survival. Autophagy is a cellular process that degrades and recycles damaged or long-lived proteins, misfolded proteins, and damaged or abnormal organelles in order to preserve homeostasis. Among the three forms of autophagy, chaperone-mediated autophagy (CMA) is distinct from macroautophagy and microautophagy; it does not require the formation of vacuoles and only degrades selected individual proteins. CMA helps to maintain cellular homeostasis by regulating protein quality, bioenergetics, and substrate-associated cellular processes at the right moment. This pathway's dysfunction has been linked to several diseases and disorders. Neurodegenerative diseases and cancer have received the most attention. In various neurodegenerative disorders, especially in their later stages, CMA activity declines. CMA has been shown to act as a tumor suppressor in cancer by destroying specific tumor promoters. Once a tumor has grown, it also helps tumor survival and the metastatic cascade. The presence of changes in CMA in these diseases disorders raises the idea of targeting CMA to restore cellular homeostasis as a potential therapeutic method. Manipulation of CMA activity may be effective therapeutic strategies for treating these diseases. Therefore, in this paper; we introduce the basic processes, regulatory mechanisms, and physiological functions of CMA; evidences supporting the role of impaired CMA function in neurodegeneration and cancer; and the potential of how targeting CMA could be a promising therapeutic method for the two diseases.
PubMed: 35734200
DOI: 10.2147/IJGM.S368364 -
Frontiers in Microbiology 2017is a good model for pexophagy research owing to its diverse pexophagy modes (macropexophagy and micropexophagy) exhibited during carbon-source shift from methanol to...
is a good model for pexophagy research owing to its diverse pexophagy modes (macropexophagy and micropexophagy) exhibited during carbon-source shift from methanol to other carbon sources. The critical condition that triggers activation of macropexophagy and micropexophagy is important for clarifying the pexophagy mechanism and human peroxisomal disorders. In this study, the pexophagy modes of were confirmed by green fluorescent protein expression and alcohol oxidase and formate dehydrogenase activities. Furthermore, intracellular energy charge (EC) was found to be a determinant of pexophagy activation. During methanol induction, the EC was about 0.5. And the final EC value was related to the pexophagy mode when carbon source switched from methanol to others. Macropexophagy and micropexophagy occurred when the EC increased to 0.6-0.75 and above 0.75, respectively. Thus, different EC values were considered as the important factor to trigger different pexophagy modes in . The results obtained in this study could help in achieving better control of the pexophagy modes to study the pexophagy mechanism.
PubMed: 28611759
DOI: 10.3389/fmicb.2017.00963 -
Methods in Cell Biology 2021Endosomal microautophagy (eMI) is a type of autophagy that allows for the selective uptake and degradation of cytosolic proteins in late endosome/multi-vesicular bodies...
Endosomal microautophagy (eMI) is a type of autophagy that allows for the selective uptake and degradation of cytosolic proteins in late endosome/multi-vesicular bodies (LE/MVB). This process starts with the recognition of a pentapeptide amino acid KFERQ-like targeting motif in the substrate protein by the hsc70 chaperone, which then enables binding and subsequent uptake of the protein into the LE/MVB compartment. The recognition of a KFERQ-like motif by hsc70 is the same initial step in chaperone-mediated autophagy (CMA), a form of selective autophagy that degrades the hsc70-targeted proteins in lysosomes in a LAMP-2A dependent manner. The shared step of substrate recognition by hsc70, originally identified for CMA, makes it now necessary to differentiate between the two pathways. Here, we detail biochemical and imaging-based methods to track eMI activity in vitro with isolated LE/MVBs and in cells in culture using fluorescent reporters and highlight approaches to distinguish whether a protein is a substrate of eMI or CMA.
Topics: Animals; Autophagy; Endosomes; HSC70 Heat-Shock Proteins; Lysosomes; Microautophagy
PubMed: 34225914
DOI: 10.1016/bs.mcb.2020.10.009 -
Developmental Cell Jun 2024Endoplasmic reticulum exit sites (ERESs) are tubular outgrowths of endoplasmic reticulum that serve as the earliest station for protein sorting and export into the...
Endoplasmic reticulum exit sites (ERESs) are tubular outgrowths of endoplasmic reticulum that serve as the earliest station for protein sorting and export into the secretory pathway. How these structures respond to different cellular conditions remains unclear. Here, we report that ERESs undergo lysosome-dependent microautophagy when Ca is released by lysosomes in response to nutrient stressors such as mTOR inhibition or amino acid starvation in mammalian cells. Targeting and uptake of ERESs into lysosomes were observed by super-resolution live-cell imaging and focus ion beam scanning electron microscopy (FIB-SEM). The mechanism was ESCRT dependent and required ubiquitinated SEC31, ALG2, and ALIX, with a knockout of ALG2 or function-blocking mutations of ALIX preventing engulfment of ERESs by lysosomes. In vitro, reconstitution of the pathway was possible using lysosomal lipid-mimicking giant unilamellar vesicles and purified recombinant components. Together, these findings demonstrate a pathway of lysosome-dependent ERES microautophagy mediated by COPII, ALG2, and ESCRTS induced by nutrient stress.
Topics: Lysosomes; Endoplasmic Reticulum; Humans; Endosomal Sorting Complexes Required for Transport; Calcium-Binding Proteins; COP-Coated Vesicles; Microautophagy; Vesicular Transport Proteins; Cell Cycle Proteins; Protein Transport; HeLa Cells; Apoptosis Regulatory Proteins; Autophagy; TOR Serine-Threonine Kinases; Calcium
PubMed: 38593803
DOI: 10.1016/j.devcel.2024.03.027 -
The International Journal of... 2019Autophagy is subdivided into chaperone-mediated autophagy, microautophagy and macroautophagy and is a highly conserved intracellular degradative pathway. It is crucial... (Review)
Review
Autophagy is subdivided into chaperone-mediated autophagy, microautophagy and macroautophagy and is a highly conserved intracellular degradative pathway. It is crucial for cellular homeostasis and also serves as a response to different stresses. Here we focus on macroautophagy, which targets damaged organelles and large protein assemblies, as well as pathogenic intracellular microbes for destruction. During this process, cytosolic material becomes enclosed in newly generated double-membrane vesicles, the so-called autophagosomes. Upon maturation, the autophagosome fuses with the lysosome for degradation of the cargo. The basic molecular machinery that controls macroautophagy works in a sequential order and consists of the ATG1 complex, the PtdIns3K complex, the membrane delivery system, two ubiquitin-like conjugation systems, and autophagy adaptors and receptors. Since the different stages of macroautophagy from initiation to final degradation of cargo are tightly regulated and highly conserved across eukaryotes, simple model organisms in combination with a wide range of techniques contributed significantly to advance our understanding of this complex dynamic process. Here, we present the social amoeba Dictyostelium discoideum as an advantageous and relevant experimental model system for the analysis of macroautophagy.
Topics: Animals; Autophagosomes; Autophagy; Caenorhabditis elegans; Class II Phosphatidylinositol 3-Kinases; Cytosol; Dictyostelium; Drosophila melanogaster; Homeostasis; Lysosomes; Phagocytosis; Saccharomyces cerevisiae; Ubiquitin
PubMed: 31840786
DOI: 10.1387/ijdb.190186LE