An autophagosome is a spherical structure with double layer membranes. It is the key structure in

macroautophagy Autophagy (or autophagocytosis; from the Ancient 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 re ...

, 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 A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...

. 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. 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. The size of autophagosomes vary between

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

s and

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...

. 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 pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist ...

, 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, ...

, autophagosomes are visible with light microscopy and can be seen as ring-shaped structures.

Autophagosome formation

The initial step of autophagosome formation of an

omegasome ] Omegasome is a Cell (biology), cell organelle consisting of lipid bilayer Biological membrane, membranes enriched for phosphatidylinositol 3-phosphate (abbreviated PI(3)P or PtdIns3P), and related to a process of autophagy. It is a subdomain of t ...

on the endoplasmic reticulum, followed by of elongation of structures called phagophores. 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. After the formation of the spherical structure, the complex of

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 autopha ...

ATG5 Autophagy related 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 ve ...

: 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 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 visu ...

, 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 endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane ca ...

or endosome-derived vesicles. These structures are then called amphisomes or intermediate autophagic vacuoles. Nonetheless, these structures contain endocytic markers even small lysosomal proteins such as

cathepsin D Cathepsin D is a protein that in humans is encoded by the ''CTSD'' gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathe ...

. The 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 aut ...

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. In yeast autophagosome maturation, there are also other known players 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 Cvt vesicles. In a non-kinase role it is - through complex formation ...

, 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, 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 cultur ...

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 spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...

. 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. Mutated ''HTT'' is the cause of Huntington's disease (HD), and has been investigated for this role and also fo ...

or its interacting partner HAP1, which colocalize with autophagosomes in neurons, are depleted.

References

{{Reflist Cell biology