An autophagosome is a spherical structure with double layer membranes. It is the key structure in
macroautophagy
Autophagy (or autophagocytosis; from the Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated ...
, the intracellular degradation system for
cytoplasmic
The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...
contents (e.g., abnormal intracellular
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, re ...
, excess or damaged
organelles
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...
, invading microorganisms). After formation, autophagosomes deliver cytoplasmic components to the
lysosomes
A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
. The outer membrane of an autophagosome fuses with a lysosome to form an autolysosome. The lysosome's
hydrolases
In biochemistry, hydrolases constitute a class of enzymes that commonly function as biochemical catalysts that use water to break a chemical bond:
:\ce \quad \xrightarrowtext\quad \ce
This typically results in dividing a larger molecule into s ...
degrade the autophagosome-delivered contents and its inner membrane.
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 ATG may refer to:
Companies
* ATG Stores, an e-tail site
* Advanced Technology Group (Apple), a former division of Apple Computer
* Advanced Technology Group (Novell), a former division of Novell
* Aviation Technology Group, the defunct developer o ...
(AuTophaGy related) family.
The size of autophagosomes varies between
mammal
A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
s and
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...
. 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 stem cells (ESCs) are Cell potency#Pluripotency, pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-Implantation (human embryo), implantation embryo. Human embryos reach the blastocyst stage 4� ...
, embryonic fibroblasts, and
hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, bile ...
, autophagosomes are visible with light microscopy and can be seen as ring-shaped structures.
Autophagosome formation
Autophagosome formation is initiated by assembly and recruitment of the core autophagy machinery to distinct cellular sites, known as phagophore assembly sites (PAS) in yeast or autophagosome formation sites in other organisms. The process is tightly regulated by multiple autophagy-related (ATG) proteins.
The ULK1/ATG1 complex is the initial activator of autophagy in response to nutrient starvation, and it recruits other ATG proteins to the PAS. The class III phosphatidylinositol 3-kinase (PI3K) complex, including VPS34 and Beclin-1, produces phosphatidylinositol 3-phosphate (PI3P), which is essential for phagophore membrane dynamics. Membrane sources for phagophore expansion may include the endoplasmic reticulum, mitochondria, Golgi apparatus, and recycling endosomes.
After the formation of the spherical structure,
ATG12
Autophagy related 12 is a protein that in humans is encoded by the ''ATG12'' gene.
Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autoph ...
-
ATG5
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 ves ...
:
ATG16L1
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 ...
or E3-like complex (E3 for short) acts as a ubiquitin-like E3 enzyme, promoting LC3/GABARAP proteins anchoring to the AP membrane.
LC3 is cleaved by
ATG4 protease to generate cytosolic LC3. The cleavage is required for the terminal fusion of an autophagosome with its target membrane. LC3 is cleaved and lipidated to form LC3-II, which associates with the autophagosomal membraneand is used as a marker of autophagosomes in
immunocytochemistry
Immunocytochemistry (ICC) is a common laboratory technique that is used to anatomically visualize the localization of a specific protein or antigen in cells by use of a specific primary antibody that binds to it. The primary antibody allows vis ...
, 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
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...
or endosome-derived vesicles and stays associated until the last moment before its fusion.
After the phagophore fully encloses its cargo, it seals and becomes a mature autophagosome. This structure then fuses with lysosomes to form an autolysosome, where the contents are degraded and recycled.
This process is similar in yeast, however the gene names differ. For example, LC3 in mammals is
Atg8
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 au ...
. In yeast autophagosomes are generated fro
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 for
amphisomesas in mammals. In yeast autophagosome maturation, there are also other known players such as
Atg1
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 Cytoplasm-to-vacuole targeting, Cvt vesicles.
In a non-kinase role it ...
, 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.
Function in neurons
In
neurons
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
, autophagosomes are generated at the
neurite
A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...
tip and mature (acidify) as they travel towards the cell body along the
axon
An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
. This axonal transport is disrupted if
huntingtin
Huntingtin (Htt) is the protein coded for in humans by the ''HTT'' gene, also known as the ''IT15'' ("interesting transcript 15") gene. Mutation, Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role an ...
or its interacting partner
HAP1, which colocalize with autophagosomes in neurons, are depleted.
Clinical relevance
Autophagosomes serve as essential carriers in the autophagy pathway, enabling cells to adapt to metabolic stress and maintain homeostasis. They are responsible for the selective degradation of damaged organelles (for example, mitophagy (mitochondria), pexophagy (peroxisomes), aggrephagy (protein aggregates), glycophagy (glycogens), lipophagy (lipids), ribophagy (ribosome), xenophagy (pathogens), and ER-phagy).
This selective removal is crucial for cellular quality control, helping prevent the accumulation of toxic proteins and damaged components. Autophagy also plays roles in development, immunity, and cell differentiation. For instance, autophagosomes assist in antigen presentation, regulate inflammatory signaling, and contribute to the elimination of intracellular bacteria and viruses.
Defects in autophagosome function have been linked to several human diseases. In addition to neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, impaired autophagy is associated with cancer, infectious diseases, and metabolic disorders like type 2 diabetes.
References
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Cell biology