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=== Infection ===
=== 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.<ref name="Gutierrez">{{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}}</ref>
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.<ref name="Gutierrez">{{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}}</ref> 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 belived to be taken up by the autophagosome from the cytosol and transfered to the endosomes where detection takes place by the 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.


=== Repair mechanism ===
=== Repair mechanism ===

Revision as of 12:26, 30 September 2009

For animals eating themselves, see self-cannibalism.

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,[1][2] 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 prevent or halt the progression of some diseases such as some types of neurodegeneration and cancer,[3] 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, meaning 'self', and phagy, 'to eat'.

Selective autophagy

Process

Macroautophagy is the sequestrating 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 (known as LC3 in mammalian cells) and the Atg4 protease on the one hand and the Atg12-Atg5-Atg16 complex on the other.[4] 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.[5]

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.[6] Mutant yeast cells that have a reduced autophagic capability rapidly perish in nutrition-deficient conditions.[7] 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.[8]

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.[9] 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 belived to be taken up by the autophagosome from the cytosol and transfered to the endosomes where detection takes place by the 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.

Repair mechanism

Autophagy degrade 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 ageing [10][11]

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.[12] 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.[13]

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.[5] Recently it has been argued that autophagy might actually be a survival mechanism on behalf of the cell.[12]

See also

References

  1. ^ Stromhaug PE, Klionsky DJ (2001). "Approaching the Molecular Mechanism of Autophagy". Traffic. 2 (8): 524-531. doi:10.1034/j.1600-0854.2001.20802.x. {{cite journal}}: More than one of |pages= and |page= specified (help)
  2. ^ Kundu M, Thompson CB (2008). "Autophagy: Basic Principles and Relevance to Disease". Annual Review of Pathology. 3: 427-455. doi:10.1146/annurev.pathmechdis.2.010506.091842.
  3. ^ Mizushima N, Klionsky DJ (2007). "Protein Turnover Via Autophagy: Implications for Metabolism". Annual Review of Nutrition. 27: 19-40. doi:10.1146/annurev.nutr.27.061406.093749.
  4. ^ Schmid D and Muenz C (2007) Innate and Adaptive Immunity through Autophagy. Immunity. 2007 Jul;27(1):11-21. Review. PMID: 17663981
  5. ^ a b Rubinsztein DC et al. (2005) Autophagy and Its Possible Roles in Nervous System Diseases, Damage and Repair. Autophagy 1(1):11-22. PMID 16874055
  6. ^ Yorimitsu T, Klionsky DJ (2005). "Autophagy: molecular machinery for self-eating". Cell Death and Differentiation (2005) 12, 1542–1552. 12: 1542–1552. doi:10.1038/sj.cdd.4401765.
  7. ^ Tsukada M, Ohsumi Y (1993). "Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae". FEBS Lett. 333: 169-174. doi:10.1016/0014-5793(93)80398-E. {{cite journal}}: More than one of |pages= and |page= specified (help)
  8. ^ M Komatsu; et al. (2005). "Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice". JCB. 169 (3): 425–434. doi:10.1083/jcb.200412022. PMID 15866887. {{cite journal}}: Explicit use of et al. in: |author= (help)
  9. ^ Gutierrez MG; et al. (2004). "Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages". Cell. 119 (6): 753-766. doi:10.1016/j.cell.2004.11.038. {{cite journal}}: Explicit use of et al. in: |author= (help); More than one of |pages= and |page= specified (help)
  10. ^ Bergamini E, Cavallini G, Donati A, Gori Z (2007). "The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction". Ann. N. Y. Acad. Sci. 1114: 69–78. doi:10.1196/annals.1396.020. PMID 17934054. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Keller JN, Dimayuga E, Chen Q, Thorpe J, Gee J, Ding Q (2004). "Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain". Int. J. Biochem. Cell Biol. 36 (12): 2376–91. doi:10.1016/j.biocel.2004.05.003. PMID 15325579. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ a b Tsujimoto Y, Shimizu S (2005). "Another way to die: autophagic programmed cell death". Cell Death and Differentiation. 12: 1528-1534. doi:10.1038/sj.cdd.4401777. {{cite journal}}: More than one of |pages= and |page= specified (help)
  13. ^ Schwartz LM; et al. (1993). "Do All Programmed Cell Deaths Occur Via Apoptosis?". Proceedings of the National Academy of Sciences. 90: 980–984. doi:10.1073/pnas.90.3.980. PMID 8430112. {{cite journal}}: Explicit use of et al. in: |author= (help)
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