Autophagy in the Eukaryotic Cell

Abstract

The major cellular pathways for protein and organelle turnover are autophagy and proteasome-mediated degradation. These processes are important to maintain a well-controlled balance between anabolism and catabolism in order to have normal cell growth and development. They play an essential role during starvation, cellular differentiation, cell death, and aging but also in preventing some types of cancer (59). These degradation pathways permit the cell to eliminate unwanted or unnecessary organelles and to recycle the components for reuse (54, 59).The lysosome or vacuole is the major catabolic factory in eukaryotic cells and contains a range of hydrolases capable of degrading all cellular constituents. Organelle turnover is accomplished exclusively at this location through a process of autophagy that is conserved among yeast, plant, and animal cells. Microautophagy involves the uptake of cytoplasm at the lysosome or vacuole surface but has not been well characterized. In contrast, degradation by macroautophagy involves membrane engulfment at an initial site that is separate from this organelle. In mammalian cells, this process has been known for a long time, but the early studies were primarily phenomenological. Molecular components have been identified in the last decade by genetic screening of the yeast Saccharomyces cerevisiae (32,80,117,121) and in recent years by two-hybrid screening of the same organism with predetermined baits or by genome-wide approaches (20,42,45,71,123). Surprisingly, molecular genetic studies with yeast have shown the overlap of the macroautophagy machinery with that used for peroxisome degradation (pexophagy) and the cytoplasm-to-vacuole targeting (Cvt) pathway (31,39,99), which ensures the delivery of the resident vacuolar protease aminopeptidase I (Ape1) (58, 97). These processes operate under different nutritional conditions, and the Cvt pathway in particular is biosynthetic. However, biochemical and morphological analyses have shown that the basic mechanism in all three processes is the sequestration of the cargo material (precursor Ape1 [prApe1], bulk cytoplasm, or specific organelle) within double-membrane structures (5-7, 39, 113).The biogenesis and consumption of these vesicles can be divided into four discrete steps: induction and cargo packaging, formation and completion, docking and fusion, and breakdown. Figure 1 shows schematically these events for macroautophagy, the Cvt pathway, and pexophagy. The induction of vesicle formation during macroautophagy is stimulated by cellular signals such as starvation (113), whereas during Cvt transport the binding of prApe1 to its receptor may be the signal that triggers induction (98). Upon completion, the sequestering vesicle (called an autophagosome or Cvt vesicle, respectively) docks with the lysosome or vacuole and then fuses with it. In this way, the inner vesicle is liberated inside the lysosome or vacuole, where it is finally consumed by hydrolases. In addition to induction, another major difference between these pathways appea...

Activation of Chaperone-mediated Autophagy during Oxidative Stress

“…In mammalian cells three different main mechanisms contribute to the degradation of intracellular components inside lysosomes (autophagy) (Dice, 2000;Reggiori and Klionsky, 2002;Wang and Klionsky, 2003; Cuervo, 2004a,b microautophagy, result in the degradation of complete regions of the cytosol, including organelles, in the lysosomal lumen. Although degradation of organelles by these autophagic pathways can be selective (i.e., specific removal of damaged mitochondria sparing normal functioning ones) (Lemasters et al, 2002), there is no evidence supporting selectivity for the degradation of soluble cytosolic proteins.…”

“…In mammalian cells three different main mechanisms contribute to the degradation of intracellular components inside lysosomes (autophagy) (Dice, 2000;Reggiori and Klionsky, 2002;Wang and Klionsky, 2003;Cuervo, 2004a,b). Two of those mechanisms, macroautophagy and Article published online ahead of print.…”

Atg27 Is Required for Autophagy-dependent Cycling of Atg9

“…One process that cells use to respond to internal or external stress is autophagy. Autophagy is a degradative process responsible for the rapid degradation of damaged or unnecessary organelles and a large portion of the cytosol in the lysosome/vacuole lumen (Reggiori and Klionsky, 2002;Klionsky, 2004). In addition, autophagy is involved in cellular remodeling, development, and aging and also plays a role in preventing a range of diseases including some types of cancer and neurodegeneration (reviewed in Shintani and Klionsky, 2004;Levine and Klionsky, 2004).…”

Duration-dependent regulation of autophagy by isoflurane exposure in aged rats

“…Autophagy is a major catabolic pathway in eukaryotic cells and is a vital pathway for degrading normal and aggregated proteins and altered or unwanted organelles, particularly under stress conditions [17] . Autophagy at an appropriate level not only plays a crucial role in protein quality control, but also acts as a defense response to stress, thus maintaining cellular homeostasis [17] .…”

“…Autophagy at an appropriate level not only plays a crucial role in protein quality control, but also acts as a defense response to stress, thus maintaining cellular homeostasis [17] . Previous studies have demonstrated that Aβ is generated in Aβ precursor protein-rich organelles during autophagic turnover [18] .…”