Autophagosome

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The autophagic process is divided into five distinct stages: Initiation, phagophore nucleation, autophagosomal formation (elongation), autophagosome-lysosome fusion (autophagolysosome) and cargo degradation. The general autophagy process (five phase).png
The autophagic process is divided into five distinct stages: Initiation, phagophore nucleation, autophagosomal formation (elongation), autophagosome-lysosome fusion (autophagolysosome) and cargo degradation.

An autophagosome is a spherical structure with double layer membranes [2] . It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles, invading microorganisms). After formation, autophagosomes deliver cytoplasmic components to the lysosomes. The outer membrane of an autophagosome fuses with a lysosome to form an autolysosome. The lysosome's hydrolases degrade the autophagosome-delivered contents and its inner membrane. [3]

Contents

The formation of autophagosomes is regulated by genes that are well-conserved from yeast to higher eukaryotes. The nomenclature of these genes has differed from paper to paper, but it has been simplified in recent years. The gene families formerly known as APG, AUT, CVT, GSA, PAZ, and PDD are now unified as the ATG (AuTophaGy related) family. [4]

The size of autophagosomes vary between mammals and yeast. Yeast autophagosomes are about 500-900 nm, while mammalian autophagosomes are larger (500-1500 nm). In some examples of cells, like embryonic stem cells, embryonic fibroblasts, and hepatocytes, autophagosomes are visible with light microscopy and can be seen as ring-shaped structures. [3]

Autophagosome formation

The initial step of autophagosome formation of an omegasome on the endoplasmic reticulum, followed by of elongation of structures called phagophores. [5]

The formation of autophagosomes is controlled by Atg genes through Atg12-Atg5 and LC3 complexes. The conjugate of Atg12-Atg5 also interacts with Atg16 to form larger complexes. Modification of Atg5 by Atg12 is essential for the elongation of the initial membrane. [6]

After the formation of the spherical structure, the complex of ATG12-ATG5:ATG16L1 dissociates from the autophagosome. LC3 is cleaved by ATG4 protease to generate cytosolic LC3. LC3 cleavage is required for the terminal fusion of an autophagosome with its target membrane. LC3 is commonly used as a marker of autophagosomes in immunocytochemistry, because it is the essential part of the vesicle and stays associated until the last moment before its fusion. At first, autophagosomes fuse with endosomes or endosome-derived vesicles. These structures are then called amphisomes or intermediate autophagic vacuoles. [7] Nonetheless, these structures contain endocytic markers even small lysosomal proteins such as cathepsin D.

The process is similar in yeast, however the gene names differ. For example, LC3 in mammals is Atg8 in yeast and autophagosomes are generated from Pre-Autophagosomal Structure (PAS) which is distinct from the precursor structures in mammalian cells. The pre-autophagosomal structure in yeast is described as a complex localized near the vacuole. However the significance of this localization is not known. Mature yeast autophagosomes fuse directly with vacuoles or lysosomes and do not form amphisomes as in mammals. [8]

In yeast autophagosome maturation, there are also other known players as Atg1, Atg13 and Atg17. Atg1 is a kinase upregulated upon induction of autophagy. Atg13 regulates Atg1 and together they form a complex called Atg13:Atg1, which receives signals from the master of nutrient sensing – Tor. Atg1 is also important in late stages of autophagosome formation. [8]

Function in neurons

In neurons, autophagosomes are generated at the neurite tip and mature (acidify) as they travel towards the cell body along the axon. [9] This axonal transport is disrupted if huntingtin or its interacting partner HAP1, which colocalize with autophagosomes in neurons, are depleted. [10]

Related Research Articles

<span class="mw-page-title-main">Autophagy</span> Process of cells digesting parts of themselves

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

<span class="mw-page-title-main">SNARE protein</span> Protein family

SNARE proteins – "SNAPREceptors" – are a large protein family consisting of at least 24 members in yeasts, more than 60 members in mammalian cells, and some numbers in plants. The primary role of SNARE proteins is to mediate the fusion of vesicles with the target membrane; this notably mediates exocytosis, but can also mediate the fusion of vesicles with membrane-bound compartments. The best studied SNAREs are those that mediate the release of synaptic vesicles containing neurotransmitters in neurons. These neuronal SNAREs are the targets of the neurotoxins responsible for botulism and tetanus produced by certain bacteria.

<span class="mw-page-title-main">Bafilomycin</span> Chemical compound

The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.

<span class="mw-page-title-main">Vojo Deretic</span> American geneticist

Vojo Deretic, is distinguished professor and chair of the Department of Molecular Genetics and Microbiology at the University of New Mexico School of Medicine. Deretic was the founding director of the Autophagy, Inflammation and Metabolism (AIM) Center of Biomedical Research Excellence. The AIM center promotes autophagy research nationally and internationally.

<span class="mw-page-title-main">Autophagy protein 5</span> Protein-coding gene in the species Homo sapiens

Autophagy protein 5 (ATG5) is a protein that, in humans, is encoded by the ATG5 gene located on chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic vesicles. It is activated by ATG7 and forms a complex with ATG12 and ATG16L1. This complex is necessary for LC3-I conjugation to PE (phosphatidylethanolamine) to form LC3-II. ATG5 can also act as a pro-apoptotic molecule targeted to the mitochondria. Under low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin.

<span class="mw-page-title-main">MAP1LC3B</span> Protein-coding gene in the species Homo sapiens

Microtubule-associated proteins 1A/1B light chain 3B is a protein that in humans is encoded by the MAP1LC3B gene. LC3 is a central protein in the autophagy pathway where it functions in autophagy substrate selection and autophagosome biogenesis. LC3 is the most widely used marker of autophagosomes.

<span class="mw-page-title-main">ATG4B</span> Protein-coding gene in the species Homo sapiens

Cysteine protease ATG4B is an enzyme that in humans is encoded by the ATG4B gene.

<span class="mw-page-title-main">ATG16L1</span> Protein-coding gene in the species Homo sapiens

Autophagy related 16 like 1 is a protein that in humans is encoded by the ATG16L1 gene. This protein is characterized as a subunit of the autophagy-related ATG12-ATG5/ATG16 complex and is essentially important for the LC3 (ATG8) lipidation and autophagosome formation. This complex localizes to the membrane and is released just before or after autophagosome completion.

<span class="mw-page-title-main">ATG12</span> Protein-coding gene in the species Homo sapiens

Autophagy related 12 is a protein that in humans is encoded by the ATG12 gene.

<span class="mw-page-title-main">ATG7</span> Protein-coding gene in the species Homo sapiens

Autophagy related 7 is a protein in humans encoded by ATG7 gene. Related to GSA7; APG7L; APG7-LIKE.

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 in 1915 by Margaret Reed Lewis and Warren Harmon 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.

<span class="mw-page-title-main">ATG8</span> Protein in budding yeast

Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for autophagy in eukaryotes. Even though there are homologues in animals, this article mainly focuses on its role in lower eukaryotes such as Saccharomyces cerevisiae.

AuTophaGy related 1 (Atg1) is a 101.7kDa serine/threonine kinase in S.cerevisiae, encoded by the gene ATG1. It is essential for the initial building of the autophagosome and Cvt vesicles. In a non-kinase role it is - through complex formation with Atg13 and Atg17 - directly controlled by the TOR kinase, a sensor for nutrient availability.

In molecular biology, autophagy related 3 (Atg3) is the E2 enzyme for the LC3 lipidation process. It is essential for autophagy. The super protein complex, the Atg16L complex, consists of multiple Atg12-Atg5 conjugates. Atg16L has an E3-like role in the LC3 lipidation reaction. The activated intermediate, LC3-Atg3 (E2), is recruited to the site where the lipidation takes place.

<span class="mw-page-title-main">Yoshinori Ohsumi</span> Japanese cell biologist

Yoshinori Ohsumi is a Japanese cell biologist specializing in autophagy, the process that cells use to destroy and recycle cellular components. Ohsumi is a professor at Tokyo Institute of Technology's Institute of Innovative Research. He received the Kyoto Prize for Basic Sciences in 2012, the 2016 Nobel Prize in Physiology or Medicine, and the 2017 Breakthrough Prize in Life Sciences for his discoveries of mechanisms for autophagy.

Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.

<span class="mw-page-title-main">Omegasome</span> Autophagy-related structure in cell biology

The omegasome is a cell organelle consisting of lipid bilayer membranes enriched for phosphatidylinositol 3-phosphate, and related to a process of autophagy. It is a subdomain of the endoplasmic reticulum (ER), and has a morphology resembling the Greek capital letter Omega (Ω). Omegasomes are the sites from which phagophores form, which are sack-like structures that mature into autophagosomes, and fuse with lysosomes in order to degrade the contents of the autophagosomes. The formation of omegasomes depends on various factors, however in general, formation of omegasomes is increased as a response to starvation, and in some biochemical situations the presence of PI(3)P leads to the formation of omegasomes.

Microautophagy is one of the three common forms of autophagic pathway, but unlike macroautophagy and chaperone-mediated autophagy, it is mediated—in mammals by lysosomal action or in plants and fungi by vacuolar action—by direct engulfment of the cytoplasmic cargo. Cytoplasmic material is trapped in the lysosome/vacuole by a random process of membrane invagination.

<span class="mw-page-title-main">Rubicon (protein)</span> Human protein involved in autophagy regulation

Rubicon is a protein that in humans is encoded by the RUBCN gene. Rubicon is one of the few known negative regulators of autophagy, a cellular process that degrades unnecessary or damaged cellular components. Rubicon is recruited to its sites of action through interaction with the small GTPase Rab7, and impairs the autophagosome-lysosome fusion step of autophagy through inhibition of PI3KC3-C2.

Atg8ylation is a process of conjugation of mammalian ATG8 proteins (mATG8s) to proteins or membranes. The process is akin to the ubiquitylation of diverse substrates by ubiquitin. There are six principal mATG8s: LC3A, LC3B, LC3C, GABARAP, GABARAPL1 and GABARAPL2. Together, they comprise a sub-class of ubiquitin-like molecules characterized by two N-terminal α-helices added to the ubiquitin core, which serve a dual role of forming a docking site for interacting proteins containing ATG8-interaction motifs and enhancing mATG8’s affinity for membranes.

References

  1. ↑ Yun, Hyeong Rok; Jo, Yong Hwa; Kim, Jieun; Shin, Yoonhwa; Kim, Sung Soo; Choi, Tae Gyu (January 2020). "Roles of Autophagy in Oxidative Stress". International Journal of Molecular Sciences. 21 (9): 3289. doi: 10.3390/ijms21093289 . ISSN   1422-0067. PMC   7246723 . PMID   32384691.
  2. ↑ Mayorga, Luis S.; Masone, Diego (2024). "The Secret Ballet Inside Multivesicular Bodies". ACS Nano. 18 (24): 15651. doi:10.1021/acsnano.4c01590.
  3. 1 2 Mizushima, N.; Ohsumi Y.; Yoshomori T. (2002). "Autophagosome Formation in Mammalian Cells". Cell Structure and Function. 27 (6): 421–429. doi: 10.1247/csf.27.421 . PMID   12576635.
  4. ↑ Klionsky, D.J.; Cregg J.M.; Dunn W.A.Jr; Emr S.D.; Sakai Y.; Sandoval I.V.; Sibirny A.; Subramani S.; Thumm M.; Veenhuis M.; Ohsumi Y. (2003). "A Unified Nomenclature for Yeast Autophagy-Related Genes" (PDF). Developmental Cell. 5 (4): 539–545. doi:10.1016/s1534-5807(03)00296-x. hdl: 11370/221542fb-cff5-4604-a588-49ee7a7c84fb . PMID   14536056.
  5. ↑ Kruppa AJ, Kendrick-Jones J, Buss F (2016). "Myosins, Actin and Autophagy". Traffic. 17 (8): 878–90. doi:10.1111/tra.12410. PMC   4957615 . PMID   27146966.
  6. ↑ Cell Signaling Technology. "Autophagy Signaling" . Retrieved 11 February 2014.
  7. ↑ Liou, W.; Geuze H.J.; Geelen M.J.H.; Slot J.W. (1997). "The Autophagic and Endocytic Pathways Converge at the Nascent Autoplasmatic Vacuoles". J Cell Biol. 136 (1): 61–70. doi:10.1083/jcb.136.1.61. PMC   2132457 . PMID   9008703.
  8. 1 2 Reggiori, F.; Klionsky D.J. (2013). "Autophagic process in Yeast: Mechanisms, Machinery and Regulation". Genetics. 194 (2): 341–361. doi:10.1534/genetics.112.149013. PMC   3664846 . PMID   23733851.
  9. ↑ Maday, S; Wallace, K. E.; Holzbaur, E. L. (2012). "Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons". The Journal of Cell Biology. 196 (4): 407–17. doi:10.1083/jcb.201106120. PMC   3283992 . PMID   22331844.
  10. ↑ Wong, Y. C.; Holzbaur, E. L. (2014). "The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation". Journal of Neuroscience. 34 (4): 1293–305. doi:10.1523/JNEUROSCI.1870-13.2014. PMC   3898289 . PMID   24453320.
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