Autophagy (cellular)


Autophagy (cellular)

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,cite journal | author=Stromhaug PE, Klionsky DJ| title=Approaching the Molecular Mechanism of Autophagy| journal=Traffic| year=2001| volume=2| issue=8| page=524-531 | pages=524 | doi=10.1034/j.1600-0854.2001.20802.x] but many questions about the actual processes and mechanisms involved still remain to be elucidated. Its role in disease is not well categorised; it may help to halt the progression of some diseases and play a protective role against infection by intracellular pathogens; however, in some situations, it may actually contribute to the development of a disease.

Etymology

Autophagy is derived from Greek roots: "auto", self, and "phagy", eating. While the use of Greek roots may be correct in using these two terms as synonyms, each is applied to different areas of study and should not be used interchangeably. One of the most exciting finds was a previously-unknown gene common to type 1 diabetes and Crohn's disease, a type of inflammatory bowel disorder, suggesting that they share similar biological pathways. The team also unexpectedly found that autophagy is important in the development of Crohn's disease.

Types

Autophagy can be broadly separated into three types: "macroautophagy", "microautophagy" and "chaperone-mediated autophagy". Macroautophagy involves the formation of a de-novo-formed membrane sealing on itself to engulf cytosolic components (proteins and/or whole organelles), which are degraded after its fusion with the lysosome, whereas microautophagy is the direct invagination of materials into the lysosome. Specific types of autophagy include:
*Chaperone-mediated autophagy, a term used to describe the degradation of specific cytosolic proteins marked with a specific peptide sequence. Chaperone molecules bind to and transport marked proteins to the lysosome via a receptor complex.
*Pexophagy, autophagy selective for degradation of peroxisomes, which can be separated into "macropexophagy" and "micropexophagy".
*Mitophagy, autophagy selective for degradation of mitochondria is called, which can be separated in "macromitophagy" and "micromitophagy".
*Xenophagy, autophagy selective for degradation of intracellular bacteria and viruses.

Process

Macroautophagy is the sequestration of organelles and long-lived proteins 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 (also known as light chain (LC)3) and the Atg4 protease on the one hand and the Atg12-Atg5-Atg16 complex on the other.Schmid D and Muenz C (2007) Innate and Adaptive Immunity through Autophagy. Immunity. 2007 Jul;27(1):11-21. Review. PMID: 17663981] 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.Rubinsztein DC et al. (2005) Autophagy and Its Possible Roles in Nervous System Diseases, Damage and Repair. Autophagy 1(1):11-22. PMID 16874055]

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:
* 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.

Functions

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.cite journal | author=Yorimitsu T, Klionsky DJ| title=Autophagy: molecular machinery for self-eating| journal=Cell Death and Differentiation (2005) 12, 1542–1552| year=2005| volume=12| url=http://www.nature.com/cdd/journal/v12/n2s/full/4401765a.html| pages=1542–1552| doi=10.1038/sj.cdd.4401765] Mutant yeast cells that have a reduced autophagic capability rapidly perish in nutrition-deficient conditions.cite journal | author=Tsukada M, Ohsumi Y| title=Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae| journal=FEBS Lett.| year=1993| volume=333| page=169-174| url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=8224160&dopt=Abstract | pages=169 | doi=10.1016/0014-5793(93)80398-E] A gene known as "Atg7" has been implicated in nutrient-mediated autophagy, as mice studies have shown that starvation-induced autophagy was impaired in "Atg7"-deficient mice.cite journal | author=M Komatsu "et al."| title=Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice| journal=JCB| year=2005| volume=169| issue=3| url=http://www.jcb.org/cgi/content/full/169/3/425#BIB41| pages=425–434| pmid=15866887| doi=10.1083/jcb.200412022]

Infection

Autophagy plays a role in the destruction of some bacteria within the cell. Intracellular pathogens such as "Mycobacterium tuberculosis" 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.cite journal | author=Gutierrez MG "et al".| title=Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages| journal=Cell| year=2004| volume=119| issue=6| page=753-766| doi=10.1016/j.cell.2004.11.038 | pages=753]

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 death; yet, no conclusive evidence exists for such a process.cite journal | author=Tsujimoto Y, Shimizu S| title=Another way to die: autophagic programmed cell death| journal=Cell Death and Differentiation| year=2005| volume=12| page=1528-1534| url=http://www.nature.com/cdd/journal/v12/n2s/full/4401777a.html | pages=1528 | doi=10.1038/sj.cdd.4401777] 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.cite journal | author=Schwartz LM, "et al"| title=Do All Programmed Cell Deaths Occur Via Apoptosis?| journal=Proceedings of the National Academy of Sciences| year=1993| volume=90| doi= 10.1073/pnas.90.3.980| pages=980–984| pmid=8430112]

It is not known whether autophagic activity in dying cells actually causes 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.

ee also

*Autophagy network
*Autophagin
*Apoptosis
*Sub-lethal damage
*Ubiquitin

External links

* [http://www.landesbioscience.com/journals/autophagy/ "Autophagy", a journal produced by Landes Bioscience and edited by DJ Klionsky]
* [http://www.longevitymeme.org/news/view_news_item.cfm?news_id=2668 LongevityMeme entry describing PubMed article on the effects of autophagy and lifespan]
* [http://www.drugs.com/dict/autophagolysosome.html Autophagolysosome on Drugs.com]

References


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