Autophagosome

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An autophagosome is a spherical structure with double layer membranes. It is a key structure in process called macroautophagy. The macroautophagy is an intracellular degradation system for the cytoplasmatic contents (abnormal intracellular proteins, excess or damage organelles) and also for invading microorganisms. After formation, autophagosome delivers cytoplasmatic components to the lysosomes. The outer membrane of autophagosome fuses with lysosome and form the autolysosome. The lysosomal’s hydrolases degrade the autophagosome-delivered contents together with its inner membrane.[1]

The formation of autophagosome is regulated by genes that are well conserved from yeast to higher eukaryota. The nomenclature of these genes differs from paper to paper. The actual nomenclature of genes involved in autophagosome formation resumed Klionsky et al. in 2003. Previously called APG, AUT, CVT, GSA, PAZ and PDD are now unified as ATG (AuTophaGy related) family.[2]

The size of autophagosome differs in mammals and in yeasts. The yeast’s autophagosome size is about 500-900nm, the mammal’s autophagosomes are much greater (0,5-1,5um). In some examples of cells (embryonic stem cells, embryonic fibroblasts, hepatocytes) we can see the autophagosomes by light microscopy as ring shaped structures.[1]

The autophagosome formation[edit]

The initial step of autophagosome formation in mammalian cells consists of elongation of small membrane structures, called initial membrane or phagophore. Tooze and Yoshimori in 2010 described a possible origin of membranes in endoplasmic reticulum or in mitochondria. But the origin of these membranes is not fully understood yet.[3]

The formation of autophagosome is controlled by Atg genes through Atg12-Atg5 and LC3 complexes. The conjugate of Atg12-Atg5 interacts also with Atg16 to form larger complexes. Modification of Atg5 by Atg12 is essential for the elongation of the initial membrane.[4]

After the formation of the spherical structure the complex of Atg12-Atg5:Atg16 dissociates from autophagosome. The LC3 is cleaved by Atg4 protease to generate cytosolic LC3. LC3 cleavage is required for the terminal fusion of autophagosome with target membrane. LC3 is commonly used as a marker of autophagosome, because it is the essential part of it and stays associated until the last moment before it’s fusion. At first autophagosome fuses with endosomes or endosome-derived vesicles and these structures are then called amphisomes or intermediate autophagic vacuoles.[5] Nonetheless these structures contain beyond endocytic markers even a little lysosomal proteins such as Cathepsin D.

The process is similar in yeasts, however the gene names differ, for example LC3 in mammals is Atg8 in yeasts. In yeast, the autophagosome is generated from Pre-Autophagosomal Structure (PAS) which is distinct from the precursor structures in mammalian cells. The pre-autophagosomal structure in yeasts is described as a structure near the vacuole. However the significance of this localization is not known. Mature autophagosome fuses directly with vacuole (functions as lysosome in yeasts) and does not form amphisomes as in mammals.[6]

In yeast autophagosome maturation are also other known players as Atg1, Atg13 and Atg17. Atg1 is a kinase upregulated upon the induction of autophagy. Atg13 regulates Atg1 and together as a complex Atg13:Atg1 receives the signal from the master of nutrient sensing – Tor. Atg1 is also important in late stages of autophagosome formation.[6]

References[edit]

  1. ^ a b Mizushima, N.; Ohsumi Y.; Yoshomori T. (2002). "Autophagosome Formation in Mammalian Cells". Cell structure and Function 27 (6): 421–429. 
  2. ^ 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". Developmental Cell 5 (4): 539–545. 
  3. ^ Tooze, S.A.; Yoshimori T. (2010). "The Origin of the Autophagosomal membrane". Nat Cell Viol. 12 (9): 831–835. 
  4. ^ Cell Signaling Technology. "Autophagy Signaling". Retrieved 2007. 
  5. ^ 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. 
  6. ^ a b Reggiori, F.; Klionsky D.J. (2013). "Autophagic process in Yeast: Mechanisms, Machinery and Regulation". Genetics 194 (2): 341–361.