Autophagy
Encyclopedia
In cell biology
, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal
machinery. It is a tightly regulated process that plays a normal part in cell growth
, development
, and homeostasis
, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes.
A variety of autophagic processes exist, all having in common the degradation of intracellular components via the lysosome. The most well-known mechanism of autophagy involves the formation of a membrane
around a targeted region of the cell, separating the contents from the rest of the cytoplasm
. The resultant vesicle then fuses with a lysosome
and subsequently degrades the contents.
It was first described in the 1960s, but many questions about the actual processes and mechanisms involved still remain to be elucidated. Its role in disease is not well categorized; it may help to prevent or halt the progression of some diseases such as some types of neurodegeneration
and cancer
, and play a protective role against infection
by intracellular pathogen
s; however, in some situations, it may actually contribute to the development of a disease.
roots: auto, meaning 'self', and phagy, 'to eat'.
s and unused long-lived protein
s in a double-membrane vesicle
, called an autophagosome or autophagic vacuole
(AV), inside the cell
. Autophagosomes form from the elongation of small membrane
structures known as autophagosome precursors. The formation of autophagosomes is initiated by class III phosphoinositide 3-kinase
and autophagy-related gene (Atg) 6 (also known as Beclin-1). In addition, two further systems are involved, composed of the ubiquitin-like protein Atg8 (known as LC3
in mammalian cells) and the Atg4 protease on the one hand and the Atg12
-Atg5
-Atg16
complex on the other. The outer membrane of the autophagosome fuses in the cytoplasm
with a lysosome
to form an autolysosome or autophagolysosome where their contents are degraded via acidic lysosomal hydrolases
.
Microautophagy, on the other hand, happens when lysosomes directly engulf cytoplasm by invaginating
, protrusion, and/or septation of the lysosomal limiting membrane.
In Chaperone-mediated autophagy, or CMA, only those proteins that have a consensus peptide sequence get recognized by the binding of a hsc70-containing chaperone/co-chaperone complex. This CMA substrate/chaperone complex then moves to the lysosomes, where the CMA receptor lysosome-associated membrane protein type-2A (LAMP-2A
) recognizes it; the protein is unfolded and translocated across the lysosome membrane assisted by the lysosomal hsc70
on the other side. CMA differs from macroautophagy and microautophagy in two main ways:
Autophagy is part of everyday normal cell growth and development wherein mTOR plays an important regulatory role.
has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired in Atg7-deficient mice.
persist within cells and block the normal actions taken by the cell to rid itself of it. Stimulating autophagy in infected cells overcomes the block and helps to rid the cell of pathogens. In addition to "simple" breakdown of pathogens, it has also been shown that at least in some cell types (plasmacytoid dendritic cells) autophagy play a role in detection of virus by the so-called pattern recognition receptors (PRR), which are part of the innate immune system. The virus (Vesicular stomatitis virus) is believed to be taken up by the autophagosome from the cytosol and translocated to the endosomes where detection takes place by a member of the PRRs called toll-like receptor 7, detecting single-stranded RNA. Following activation of the toll-like receptor, intracellular signalling cascades are initiated, leading to induction of interferon, among other anti-viral cytokines. A subset of viruses and bacteria subvert the autophagic pathway to promote their own replication. (http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030156)
; yet, no conclusive evidence exists for such a process. Nevertheless, observations that cells possessing autophagic features in areas undergoing programmed cell death have led to the coining of the phrase autophagic cell death (also known as cytoplasmic cell death or type II cell death). Studies of the metamorphosis
of insects have shown cells undergoing a form of programmed cell death that appears distinct from other forms; these have been proposed as examples of autophagic cell death.
It is not known whether autophagic activity in dying cells actually causes cell death or whether it simply occurs as a process alongside it. In many neurological diseases, in certain neuronal cell death pathways and after neuronal injury, there are increased numbers of autophagosomes. A causative relationship between autophagy and cell death has not been established. It is unclear whether the increase in autophagosomes indicates an increase in autophagic activity or decreased autophagosome-lysosome fusion. Recently it has been argued that autophagy might actually be a survival mechanism on behalf of the cell.
, and a possible explanation for neutropenia
.
Certain diets
utilize a form of autophagia. The Atkins Diet relies heavily on ketosis
as a method of reducing body fat, which, in itself, could be considered a form of cellular autophagia.
, Harvard School of Dental Medicine
, and the Harvard School of Public Health
):
"Researchers have discovered a small molecule
that disables a prized cancer target, one that many pharmaceutical and biotech companies have been investigating for years.
The findings, which also establish a chain linking the target to the tumor-suppressing gene p53
, suggest a long-sought weapon against the defenses of cancer cells.
The results were published in the journal "Cell
".
The process, called autophagy, rids cells of debris and is crucial for cell survival.
“Autophagy helps cells survive stress,” said Junying Yuan, Harvard Medical School professor of cell biology
and senior author on the paper. “It’s like a recycling
process that degrades old proteins into amino acid
energy sources enabling cells to survive in difficult circumstances. It’s a turnover mechanism.”
When autophagy falters, life span
shortens, and cancer and other diseases, such as neurodegeneration
, can ensue. One such defect, in a gene called Beclin1, decreases autophagy in mammalian cells, and researchers have suspected that this leads to increased prostate and breast cancers.
But like so many cancer factors, autophagy can be a double-edged sword.
When a patient is undergoing treatment such as chemotherapy
, cancer cells co-opt autophagy and use it to survive the stress of therapy. Researchers have reasoned that in certain clinical settings, briefly disabling autophagy may support and enhance treatment.
For years, pharmaceutical companies have sought to do just that. The challenge lay in identifying the precise target within a protein complex. Yuan and her colleagues developed a cell-based screening platform in which they uncovered a key mechanism of autophagy as well as a small molecule that efficiently blocks the process by degrading the protein complex that autophagy depends on. The protein beclin1, encoded by the Beclin1 gene already linked to autophagy, is a part of this complex.
They named the molecule spautin-1, for specific and potent autophagy inhibitor-1.
Drilling deeper, the researchers found that spautin-1 blocked the activity of USP10
, a molecule that offers a kind of “stay of execution” for proteins on death row. Proteins marked for disposal are tagged with a marker called ubiquitin
, and USP10 often removes this tag from select proteins, sparing them. Removing USP10 leaves these proteins vulnerable.
Beclin1, it turns out, regulates the activity of USP10. And the researchers connected these findings to other studies linking USP10 to p53, a gene widely known to suppress cancer.
“Knocking down Beclin1, which our small molecule does, knocks down USP10, which in turn knocks down p53,” said Yuan. “They are all part of a chain.”
This then explains the earlier observation that mammals with defective Beclin1 experience increased cancer. When beclin1 is diminished, p53, which is downstream, is also diminished, and cancer thrives. However, when Beclin1 is removed altogether, the cell dies. This discovery suggests that selectively targeting autophagy during cancer therapies may greatly benefit patients.
Yuan is now collaborating with researchers at the company Roche
, based in Basel, Switzerland and at BioBay, based in Suzhou, China, to translate these findings into potential therapies.
This research was funded by the National Institutes of Health
, the Chinese Academy of Sciences
, the National Natural Science Foundation of China
, and the Harvard University Biomedical Accelerator Fund.
—David Cameron
One Response to Long Sought Cancer"
Cell biology
Cell biology is a scientific discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level...
, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
machinery. It is a tightly regulated process that plays a normal part in cell growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
, development
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, and homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes.
A variety of autophagic processes exist, all having in common the degradation of intracellular components via the lysosome. The most well-known mechanism of autophagy involves the formation of a membrane
Biological membrane
A biological membrane or biomembrane is an enclosing or separatingmembrane that acts as a selective barrier, within or around a cell. It consists of a lipid bilayer with embedded proteins that may constitute close to 50% of membrane content...
around a targeted region of the cell, separating the contents from the rest of the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. The resultant vesicle then fuses with a lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
and subsequently degrades the contents.
It was first described in the 1960s, but many questions about the actual processes and mechanisms involved still remain to be elucidated. Its role in disease is not well categorized; it may help to prevent or halt the progression of some diseases such as some types of neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, and play a protective role against infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
by intracellular pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s; however, in some situations, it may actually contribute to the development of a disease.
Etymology
Autophagy is derived from GreekGreek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...
roots: auto, meaning 'self', and phagy, 'to eat'.
Selective autophagy
- Pexophagy, autophagy selective for degradationChemical decompositionChemical decomposition, analysis or breakdown is the separation of a chemical compound into elements or simpler compounds. It is sometimes defined as the exact opposite of a chemical synthesis. Chemical decomposition is often an undesired chemical reaction...
of peroxisomes, which can be separated into macropexophagy and micropexophagy. - Mitophagy, autophagy selective for degradation of mitochondria, which can be separated into macromitophagy and micromitophagy.
- Xenophagy, autophagy selective for degradation of intracellular bacteriaBacteriaBacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and viruses (foreign bodies). - Aggrephagy, autophagy selective for protein aggregates.
- Reticulophagy, autophagy selective for endoplasmic reticulumEndoplasmic reticulumThe endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. - Heterophagy, autophagy selective for endosomes.
- Crinophagy, autophagy selective for golgi apparatusGolgi apparatusThe Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
. - Ribophagy, autophagy selective for ribosomes.
Process
Macroautophagy sequestrates damaged organelleOrganelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s and unused long-lived protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s in a double-membrane vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
, called an autophagosome or autophagic vacuole
Vacuole
A vacuole is a membrane-bound organelle which is present in all plant and fungal cells and some protist, animal and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic molecules including enzymes in solution, though in certain...
(AV), inside the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. Autophagosomes form from the elongation of small membrane
Biological membrane
A biological membrane or biomembrane is an enclosing or separatingmembrane that acts as a selective barrier, within or around a cell. It consists of a lipid bilayer with embedded proteins that may constitute close to 50% of membrane content...
structures known as autophagosome precursors. The formation of autophagosomes is initiated by class III phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
and autophagy-related gene (Atg) 6 (also known as Beclin-1). In addition, two further systems are involved, composed of the ubiquitin-like protein Atg8 (known as LC3
MAP1LC3A
Microtubule-associated proteins 1A/1B light chain 3A is a protein that in humans is encoded by the MAP1LC3A gene.. MAPLC3A is the mammalian homologue of yeast ATG8, an important marker and effector of autophagy.-Interactions:...
in mammalian cells) and the Atg4 protease on the one hand and the Atg12
ATG12
Autophagy-related protein 12 is a protein that in humans is encoded by the ATG12 gene.-Further reading:...
-Atg5
ATG5
Autophagy protein 5 is a protein that in humans is encoded by the ATG5 gene.-Further reading:...
-Atg16
ATG16L1
Autophagy-related protein 16-1 is a protein that in humans is encoded by the ATG16L1 gene.-Function:Autophagy is the major intracellular degradation system delivering cytoplasmic components to lysosomes, and it accounts for degradation of most long-lived proteins and some organelles...
complex on the other. The outer membrane of the autophagosome fuses in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
with a lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
to form an autolysosome or autophagolysosome where their contents are degraded via acidic lysosomal hydrolases
Acid hydrolase
An acid hydrolase is an enzyme that works best at acidic pHs. It is commonly located in lysosomes, which are acidic on the inside. Acid hydrolases may be nucleases, proteases, glycosidases, lipases, phosphatases, sulfatases and phospholipases and make up the approximately 50 degradative enzymes of...
.
Microautophagy, on the other hand, happens when lysosomes directly engulf cytoplasm by invaginating
Invagination
Invagination means to fold inward or to sheath. In biology, this can refer to a number of processes.* Invagination is the morphogenetic processes by which an embryo takes form, and is the initial step of gastrulation, the massive reorganization of the embryo from a simple spherical ball of cells,...
, protrusion, and/or septation of the lysosomal limiting membrane.
In Chaperone-mediated autophagy, or CMA, only those proteins that have a consensus peptide sequence get recognized by the binding of a hsc70-containing chaperone/co-chaperone complex. This CMA substrate/chaperone complex then moves to the lysosomes, where the CMA receptor lysosome-associated membrane protein type-2A (LAMP-2A
LAMP2
Lysosomal-associated membrane protein 2 also known as CD107b , is a human gene....
) recognizes it; the protein is unfolded and translocated across the lysosome membrane assisted by the lysosomal hsc70
Hsc70
Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the HSPA8 gene.- Function :...
on the other side. CMA differs from macroautophagy and microautophagy in two main ways:
- The substrates are translocated across the lysosome membrane on a one-by-one basis, whereas in the macroautophagy and microautophagy the substrates are engulfed or sequestered in-bulk.
- CMA is very selective in what it degrades and can degrade only certain proteins and not organelles.
Autophagy is part of everyday normal cell growth and development wherein mTOR plays an important regulatory role.
Nutrient starvation
During nutrient starvation, increased levels of autophagy lead to the breakdown of non-vital components and the release of nutrients, ensuring that vital processes can continue. Mutant yeast cells that have a reduced autophagic capability rapidly perish in nutrition-deficient conditions. A gene known as Atg7ATG7
Autophagy-related protein 7 is a protein that in humans is encoded by the ATG7 gene.-Further reading:...
has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired in Atg7-deficient mice.
Infection
Autophagy plays a role in the destruction of some bacteria within the cell. Intracellular pathogens such as Mycobacterium tuberculosisMycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
persist within cells and block the normal actions taken by the cell to rid itself of it. Stimulating autophagy in infected cells overcomes the block and helps to rid the cell of pathogens. In addition to "simple" breakdown of pathogens, it has also been shown that at least in some cell types (plasmacytoid dendritic cells) autophagy play a role in detection of virus by the so-called pattern recognition receptors (PRR), which are part of the innate immune system. The virus (Vesicular stomatitis virus) is believed to be taken up by the autophagosome from the cytosol and translocated to the endosomes where detection takes place by a member of the PRRs called toll-like receptor 7, detecting single-stranded RNA. Following activation of the toll-like receptor, intracellular signalling cascades are initiated, leading to induction of interferon, among other anti-viral cytokines. A subset of viruses and bacteria subvert the autophagic pathway to promote their own replication. (http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030156)
Repair mechanism
Autophagy degrades damaged organelles, cell membranes and proteins, and the failure of autophagy is thought to be one of the main reasons for the accumulation of cell damage and aging.Programmed cell death
It has been proposed that autophagy resulting in the total destruction of the cell is one of several types of programmed cell deathProgrammed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
; yet, no conclusive evidence exists for such a process. Nevertheless, observations that cells possessing autophagic features in areas undergoing programmed cell death have led to the coining of the phrase autophagic cell death (also known as cytoplasmic cell death or type II cell death). Studies of the metamorphosis
Metamorphosis
Metamorphosis is a biological process by which an animal physically develops after birth or hatching, involving a conspicuous and relatively abrupt change in the animal's body structure through cell growth and differentiation...
of insects have shown cells undergoing a form of programmed cell death that appears distinct from other forms; these have been proposed as examples of autophagic cell death.
It is not known whether autophagic activity in dying cells actually causes cell death or whether it simply occurs as a process alongside it. In many neurological diseases, in certain neuronal cell death pathways and after neuronal injury, there are increased numbers of autophagosomes. A causative relationship between autophagy and cell death has not been established. It is unclear whether the increase in autophagosomes indicates an increase in autophagic activity or decreased autophagosome-lysosome fusion. Recently it has been argued that autophagy might actually be a survival mechanism on behalf of the cell.
Examples
Autophagia can occur in body cells as a method of sustaining the life of a cell. Alternatively, the term could apply to an organism recycling tissue for sustenance. In myeloid precursor cells, autophagia can be an indicator of CHSChédiak-Higashi syndrome
Chédiak–Higashi syndrome is a rare autosomal recessive disorder that arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism and peripheral neuropathy...
, and a possible explanation for neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
.
Certain diets
Dieting
Dieting is the practice of eating food in a regulated fashion to achieve or maintain a controlled weight. In most cases dieting is used in combination with physical exercise to lose weight in those who are overweight or obese. Some athletes, however, follow a diet to gain weight...
utilize a form of autophagia. The Atkins Diet relies heavily on ketosis
Ketosis
Ketosis is a state of elevated levels of ketone bodies in the body. It is almost always generalized throughout the body, with hyperketonemia, that is, an elevated level of ketone bodies in the blood. Ketone bodies are formed by ketogenesis when the liver glycogen stores are depleted...
as a method of reducing body fat, which, in itself, could be considered a form of cellular autophagia.
Academic research concerning oncological pharmacology and autophagy
According to a Wednesday, November 9, 2011 online news article (the story was released by David Cameron of FOCUS, which publishes news from Harvard Medical SchoolHarvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
, Harvard School of Dental Medicine
Harvard School of Dental Medicine
Harvard School of Dental Medicine is one of the graduate schools of Harvard University. It is an American dental school located in the Longwood Medical Area in Boston, Massachusetts. In addition to the DMD degree, HSDM offers specialty training programs, advanced training programs, a Ph.D...
, and the Harvard School of Public Health
Harvard School of Public Health
The Harvard School of Public Health is one of the professional graduate schools of Harvard University, located in the Longwood Area of the Boston, Massachusetts neighborhood of Mission Hill, which is next to Harvard Medical School. HSPH is considered a significant school focusing on health in the...
):
"Researchers have discovered a small molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
that disables a prized cancer target, one that many pharmaceutical and biotech companies have been investigating for years.
The findings, which also establish a chain linking the target to the tumor-suppressing gene p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, suggest a long-sought weapon against the defenses of cancer cells.
The results were published in the journal "Cell
Cell
-Science and technology:*Cell , the functional basic unit of life*Cell , a term used in an electronic circuit design schematics*Cell , a three-dimensional element, part of a higher-dimensional object*Cell , a scientific journal...
".
The process, called autophagy, rids cells of debris and is crucial for cell survival.
“Autophagy helps cells survive stress,” said Junying Yuan, Harvard Medical School professor of cell biology
Cell biology
Cell biology is a scientific discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level...
and senior author on the paper. “It’s like a recycling
Recycling
Recycling is processing used materials into new products to prevent waste of potentially useful materials, reduce the consumption of fresh raw materials, reduce energy usage, reduce air pollution and water pollution by reducing the need for "conventional" waste disposal, and lower greenhouse...
process that degrades old proteins into amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
energy sources enabling cells to survive in difficult circumstances. It’s a turnover mechanism.”
When autophagy falters, life span
Life span
Life span or lifespan may refer to:*Maximum life span, the maximum lifespan observed in a group*Life expectancy, the average lifespan expected of a group*Longevity, the average lifespan expected under ideal conditions...
shortens, and cancer and other diseases, such as neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
, can ensue. One such defect, in a gene called Beclin1, decreases autophagy in mammalian cells, and researchers have suspected that this leads to increased prostate and breast cancers.
But like so many cancer factors, autophagy can be a double-edged sword.
When a patient is undergoing treatment such as chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, cancer cells co-opt autophagy and use it to survive the stress of therapy. Researchers have reasoned that in certain clinical settings, briefly disabling autophagy may support and enhance treatment.
For years, pharmaceutical companies have sought to do just that. The challenge lay in identifying the precise target within a protein complex. Yuan and her colleagues developed a cell-based screening platform in which they uncovered a key mechanism of autophagy as well as a small molecule that efficiently blocks the process by degrading the protein complex that autophagy depends on. The protein beclin1, encoded by the Beclin1 gene already linked to autophagy, is a part of this complex.
They named the molecule spautin-1, for specific and potent autophagy inhibitor-1.
Drilling deeper, the researchers found that spautin-1 blocked the activity of USP10
USP10
Ubiquitin specific peptidase 10, also known as USP10, is an enzyme which in humans is encoded by the USP10 gene.- Function :Ubiquitin is a highly conserved protein that is covalently linked to other proteins to regulate their function and degradation. This gene encodes a member of the...
, a molecule that offers a kind of “stay of execution” for proteins on death row. Proteins marked for disposal are tagged with a marker called ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
, and USP10 often removes this tag from select proteins, sparing them. Removing USP10 leaves these proteins vulnerable.
Beclin1, it turns out, regulates the activity of USP10. And the researchers connected these findings to other studies linking USP10 to p53, a gene widely known to suppress cancer.
“Knocking down Beclin1, which our small molecule does, knocks down USP10, which in turn knocks down p53,” said Yuan. “They are all part of a chain.”
This then explains the earlier observation that mammals with defective Beclin1 experience increased cancer. When beclin1 is diminished, p53, which is downstream, is also diminished, and cancer thrives. However, when Beclin1 is removed altogether, the cell dies. This discovery suggests that selectively targeting autophagy during cancer therapies may greatly benefit patients.
Yuan is now collaborating with researchers at the company Roche
Roche
Roche is French for "boulder/rock". The word is several names:-Business & companies:* Hoffmann–La Roche AG, Basel, Switzerland, one of the largest pharmaceutical companies in the world....
, based in Basel, Switzerland and at BioBay, based in Suzhou, China, to translate these findings into potential therapies.
This research was funded by the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
, the Chinese Academy of Sciences
Chinese Academy of Sciences
The Chinese Academy of Sciences , formerly known as Academia Sinica, is the national academy for the natural sciences of the People's Republic of China. It is an institution of the State Council of China. It is headquartered in Beijing, with institutes all over the People's Republic of China...
, the National Natural Science Foundation of China
National Natural Science Foundation of China
The National Natural Science Foundation of China is an organization directly affiliated to the State Council for the management of the National Natural Science Fund.-History:NSFC was founded in February 1986 with the approval of the State Council...
, and the Harvard University Biomedical Accelerator Fund.
—David Cameron
One Response to Long Sought Cancer"
See also
- Autophagy databaseAutophagy databaseThe Autophagy database is a database of proteins involved in autophagy, a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. Its molecular mechanisms have not been fully elucidated, despite dramatic advances in the field as evidenced by hundreds...
- AutophaginAutophaginAutophagin-1 is a unique cysteine protease responsible for the cleavage of the carboxyl terminus of Atg8/Apg8/Aut7, a reaction essential for its lipidation during autophagy...
- ApoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
- Sub-lethal damageSub-lethal damageCell damage is damage to any of the components of the cell.-Sub-lethal damage:If damage to a cell is minimal, the cell can recover following removal of the damaging stimulus. Damaged proteins and organelles are removed by a cell stress response and autophagy with new structural components being...
- UbiquitinUbiquitinUbiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
External links
- Autophagy, a journal produced by Landes Bioscience and edited by DJ Klionsky
- LongevityMeme entry describing PubMed article on the effects of autophagy and lifespan
- Autophagolysosome on Drugs.com
- HADb, a Human Autophagy dedicated Database
- Autophagy DB, an autophagy database that covers all eukaryotes
- Self-Destructive Behavior in Cells May Hold Key to a Longer Life