Instruct: Given a question, retrieve relevant documents that can help answer the question.
Query: Who first identified the process of autophagy?
The name "autophagy" was coined by Belgian biochemist Christian de Duve in 1963 based on his discovery of the functions of lysosome.[3] The identification of autophagy-related genes in yeast in the 1990s let researchers figure out the mechanisms of autophagy,[8][9][10][11][12] which eventually led to the award of the 2016 Nobel Prize in Physiology or Medicine to Japanese researcher Yoshinori Ohsumi.[13]
Since dysregulation of autophagy is involved in the pathogenesis of a broad range of diseases, great efforts are invested to identify and characterize small synthetic or natural molecules that can regulate it.[101]
The first strategy has been tested by looking at dose-response anti-tumor effects during autophagy-induced therapies. These therapies have shown that autophagy increases in a dose-dependent manner. This is directly related to the growth of cancer cells in a dose-dependent manner as well.[93][96] This data supports the development of therapies that will encourage autophagy. Secondly, inhibiting the protein pathways directly known to induce autophagy may also serve as an anticancer therapy.[94][96]
Human autophagy database is a product of the Luxembourg Institute of Health (LIH). LIH has several branches throughout Luxembourg available for Biomonitoring, Infection and Immunity, Health administration, Oncology, Sports Medicine, and Biobank. Each of these departments aims to support the LIH mission statement, which is "to generate and translate research knowledge into clinical applications with an impact on the future challenges of health care and personalised medicine." It accomplishes these aims by working toward the forefront of biomedical research, by maintaining excellence, integrity, and passion in their work and offered tools. The Laboratory of Experimental Cancer Research of LIH helped to establish one of these tools, that tool being the database known as Human autophagy database.
Human autophagy database (HADb) is another available autophagy resource. Unlike Autophagy database, Human autophagy database only compares those proteins found in humans. HADb is the first human-only autophagy database, where researchers may find an updated listing of directly and indirectly related autophagic proteins, given no consistent database previously available to compensate for a huge expansion in autophagy research. HADb does not only provide information on the gene of interest, but also aims to evolve into a database which can be used to analyze the gene of interest. For this purpose, HADb was made as complete as possible in terms of autophagy-related proteins, though newly discovered proteins and genes may be submitted by different users to the "Submission" section. The information provided by Human autophagy database can be used further in bioinformatics applications.
Numerous studies have shown the pathways and associations between ROS levels and apoptosis, but a newer line of study has connected ROS levels and autophagy. ROS can also induce cell death through autophagy, which is a self-catabolic process involving sequestration of cytoplasmic contents (exhausted or damaged organelles and protein aggregates) for degradation in lysosomes. Therefore, autophagy can also regulate the cell’s health in times of oxidative stress. Autophagy can be induced by ROS levels through many different pathways in the cell in an attempt to dispose of harmful organelles and prevent damage, such as carcinogens, without inducing apoptosis. Autophagic cell death can be prompted by the over expression of autophagy where the cell digests too much of itself in an attempt to minimize the damage and can no longer survive. When this type of cell death occurs, an increase or loss of control of autophagy regulating genes is commonly co-observed. Thus, once a more in-depth understanding of autophagic cell death is attained and its relation to ROS, this form of programmed cell death may serve as a future cancer therapy.
Autophagy and apoptosis are two different cell death mechanisms brought on by high levels of ROS in the cells, however; autophagy and apoptosis rarely act through strictly independent pathways. There is a clear connection between ROS and autophagy and a correlation seen between excessive amounts of ROS leading to apoptosis. The depolarization of the mitochondrial membrane is also characteristic of the initiation of autophagy. When mitochondria are damaged and begin to release ROS, autophagy is initiated to dispose of the damaging organelle. If a drug targets mitochondria and creates ROS, autophagy may dispose of so many mitochondria and other damaged organelles that the cell is no longer viable. The extensive amount of ROS and mitochondrial damage may also signal for apoptosis. The balance of autophagy within the cell and the crosstalk between autophagy and apoptosis mediated by ROS is crucial for a cell’s survival. This crosstalk and connection between autophagy and apoptosis could be a mechanism targeted by cancer therapies or used in combination therapies for highly resistant cancers.
Because autophagy decreases with age and age is a major risk factor for osteoarthritis, the role of autophagy in the development of this disease is suggested. Proteins involved in autophagy are reduced with age in both human and mouse articular cartilage.[85] Mechanical injury to cartilage explants in culture also reduced autophagy proteins.[86] Autophagy is constantly activated in normal cartilage but it is compromised with age and precedes cartilage cell death and structural damage.[87] Thus autophagy is involved in a normal protective process (chondroprotection) in the joint.
In October 2001, Cuervo accepted a faculty position at the Albert Einstein College of Medicine in The Bronx, New York. She then began primarily focusing on chaperone-mediated autophagy and its role in aging and human disease. Her research lab focused on protein translocations across lysosomal membranes, identifying regulator proteins like glial fibrillary acidic protein. In collaboration with neuroscientist David Sulzer of Columbia University Medical Center, she published evidence of altered chaperone-mediated autophagy in Parkinson's Disease. Similar findings of disrupted autophagy was also reported when Huntington Disease was studied. Cuervo's research team also identified LRRK2, a protein enzyme that becomes mutated in Parkinson's disease, disrupts the process of translocation across lysosomal membranes.
Self-cannibalism is the practice of eating oneself, also called autocannibalism, or autosarcophagy. A similar term which is applied differently is "autophagy", which specifically denotes the normal process of self-degradation by cells. While almost an exclusive term for this process, autophagy nonetheless has occasionally made its way into more common usage.
The Autophagy, Inflammation and Metabolism (AIM) center is an NIH-funded Center of Biomedical Research Excellence focused on the study of autophagy as a fundamental biological process and how it intersects with metabolism and quality control processes in eukaryotic cells. A special emphasis is on the role or autophagy in a wide spectrum of diseases with metabolic, inflammatory and immunological aspects. At the fundamental level, autophagy is a cytoplasmic pathway for the disposal of damaged or surplus organelles such as mitochondria, peroxisomes, lysosomes, endoplasmic reticulum, ribosomes, protein aggregates and also serves as a catabolic process providing nutrients through autodigestion at times of starvation. Autophagy has been implicated in cancer, neurodegeneration such as Alzheimer's disease, Huntington's disease and Parkinson's disease, diabetes, development, infections and immune diseases, as well as a process of relevance for aging.
Autophagy and apoptosis are connected both positively and negatively, and extensive crosstalk exists between the two. During nutrient deficiency, autophagy functions as a pro-survival mechanism, however, excessive autophagy may lead to cell death, a process morphologically distinct from apoptosis. Several pro-apoptotic signals, such as TNF, TRAIL, and FADD, also induce autophagy. Additionally, Bcl-2 inhibits Beclin-1-dependent autophagy, thereby functioning both as a pro-survival and as an anti-autophagic regulator.
mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level. Because autophagy appears to decline with age, activation of autophagy may help promote longevity in humans. Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.
New developments in research have found that targeted autophagy may be a viable therapeutic solution in fighting cancer. As discussed above, autophagy plays both a role in tumor suppression and tumor cell survival. Thus, the qualities of autophagy can be used as a strategy for cancer prevention. The first strategy is to induce autophagy and enhance its tumor suppression attributes. The second strategy is to inhibit autophagy and thus induce apoptosis.[94]
Atg8 is one of the key molecular components involved in autophagy, the cellular process mediating the lysosome/vacuole-dependent turnover of macromolecules and organelles. Autophagy is induced upon nutrient depletion or rapamycin treatment and leads to the response of more than 30 autophagy-related (ATG) genes known so far, including ATG8.
How exactly ATG proteins are regulated is still under investigation, but it is clear that all signals reporting on the availability of carbon and nitrogen sources converge on the TOR signalling pathway and that ATG proteins are downstream effectors of this pathway. In case nutrient supplies are sufficient, the TOR signaling pathway hyperphosphorylates certain Atg proteins, thereby inhibiting autophagosome formation. After starvation autophagy is induced through the activation of Atg proteins both on the protein modification and the transcriptional level.
Atg8 is especially important in macroautophagy which is one of three distinct types of autophagy characterized by the formation of double-membrane enclosed vesicles that sequester portions of the cytosol, the so-called autophagosomes. The outer membrane of these autophagosomes subsequently fuses with the lysosome/vacuole to release an inter single membrane (autophagic body) destined for degradation. During this process, Atg8 is particularly crucial for autophagosome maturation (lipidation).
Rubinsztein has made major contributions to the field of neurodegeneration with his laboratory's discovery that autophagy regulates the levels of intracytoplasmic aggregate-prone proteins that cause many neurodegenerative diseases, including Huntington's, Parkinson's and Alzheimer's disease. His lab has found that autophagy may be inhibited in various neurodegenerative diseases and has elucidated the pathological consequences of autophagy compromise. In addition his research has advanced the basic understanding of autophagy, identifying the plasma membrane as a source of autophagosome membrane and characterising early events in autophagosome biogenesis. Furthermore, he studied how lysosomal positioning regulates autophagy. His goal is to understand the links between these diseases and autophagy. He is currently focused on understanding how to induce autophagy in vivo to remove toxic proteins and avoid the development of neurodegenerative disease
Autophagy then occurs at an accelerated rate. In autophagy, cells cannibalize critical molecules to produce amino acids for gluconeogenesis. This process distorts the structure of the cells, and a common cause of death in starvation is due to diaphragm failure from prolonged autophagy.
Autophagy database is a product of the National Institute of Genetics (NIG) NIG was founded in June 1949 by the ministry of Education, Science, Sports, and Culture, with Prof. Kan Oguma being elected the first director. Over time, many departments have been added for various applications such as Genetics, Genomics, DNA Research, and, most notably for our purposes, the DNA Data Bank. NIG is a division of the Japanese Research Organization of Information and Systems, and is currently under the supervision of its ninth director. NIG aims to conduct top-level research in the pursuit of streamlining of information, as well as the dissemination of information from research into societal application. A tool created by this organization for this purpose is the Autophagy database.
The Autophagy database is a database of proteins involved in autophagy. The Autophagy database intends to collect all relevant information, organize it, and make it publicly available so that its users can easily get up-to-date knowledge. Specifically, the Autophagy database offers a "free-for-all" tool for those with interests, research and otherwise, in autophagy. To better accomplish this aim, the available Autophagy database from NIG calls for users of the database to disseminate and share information, so that autophagy-related data can be available for free to all who need it. For an interested research community, this model of research dissemination holds promise. As of , there were 582 reviewed proteins available in this database. Including autophagic proteins available in HomoloGene, NCBI, there are over 52,000 total proteins. Autophagy database offers comparison of homologous proteins between 41 different species to search new and old autophagy-related proteins, so that current autophagy research can be streamlined. The database was made publicly available in March 2010 and currently includes 7,444 genes/proteins in 82 eukaryotes.
Christian de Duve coined the term autophagy in 1963 whereas Ohsumi began his work in 1988. Prior to that time, less than 20 papers per year were published on this subject. During the 1990s, Ohsumi's group described the morphology of autophagy in yeast, and performed mutational screening on yeast cells that identified essential genes for cells to be capable of autophagy.
Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.
Autophagy (Greek: ‘self-eating’) was initially identified as a catabolic process for the unselective degradation of cellular content in lysosomes under starvation conditions. However, autophagy also comprises selective degradation pathways, which depend on ubiquitin conjugation to initiate sorting to lysosomes. In the case of chaperone-assisted selective autophagy, dysfunctional, nonnative proteins are recognized by molecular chaperones and become ubiquitinated by chaperone-associated ubiquitin ligases. The ubiquitinated proteins are enclosed in autophagosomes, which eventually fuse with lysosomes, leading to the degradation of the dysfunctional proteins. Chaperone-assisted selective autophagy is a vital part of the cellular protein quality control system. It is essential for protein homeostasis (proteostasis) in neurons and in mechanically strained cells and tissues such as skeletal muscle, heart and lung.
The first autophagy genes were identified by genetic screens conducted in Saccharomyces cerevisiae.[8][9][10][11][12] Following their identification those genes were functionally characterized and their orthologs in a variety of different organisms were identified and studied.[6][45]
Macroautophagy, often referred to as autophagy, is a catabolic process that results in the autophagosomic-lysosomal degradation of bulk cytoplasmic contents, abnormal protein aggregates, and excess or damaged organelles. Autophagy is generally activated by conditions of nutrient deprivation but has also been associated with physiological as well as pathological processes such as development, differentiation, neurodegenerative diseases, stress, infection and cancer.
Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Lewis and Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.
LC3 was originally identified as a microtubule associated protein in rat brain. However it was later found that the primary function of LC3 is in autophagy, a process that involves the bulk degradation of cytoplasmic components.
Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
One main function of Atg4 is to cleave the pre-protein of Atg8, leading to the non-lipidated soluble (-I) form which can be processed further by Atg3, Atg7, Atg5-12 into the lipidated form (-II) anchored to the autophagic membrane.
There are three main types of autophagy, namely macroautophagy, microautophagy and Chaperone mediated autophagy. They are mediated by the autophagy-related genes and their associated enzymes.[6][7][27][28][29] Macroautophagy is then divided into bulk and selective autophagy. In the selective autophagy is the autophagy of organelles; mitophagy,[30] lipophagy,[31] pexophagy,[32] chlorophagy,[33] ribophagy[34] and others.