Levine review - How is autophagy induced Autophagy occurs...

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Unformatted text preview: How is autophagy induced? Autophagy occurs when cells need to ‘self- cannibalize’ or degrade their constituents. Underlying ‘housekeeping’ levels of autophagy probably occur in most normal cells to pre- vent the accumulation of protein aggregates and defective cellular substructures. Cer- tain environmental cues (such as starvation, high temperature, low oxygen, hormonal stimulation) or intracellular stress (damaged organelles, accumulation of mutant proteins, microbial invasion) activate signalling path- ways that increase autophagy. Classically, most research on how autophagy is induced has focused on an enzyme called TOR kinase. This enzyme is a sensor of nutrient status and a master regulator of cell growth; it negatively regulates autophagy through its effects on a set of proteins known as autophagy-execution proteins. However, it is now clear that numer- ous signalling pathways, such as those involved in the control of cell growth, DNA-damage repair, a form of programmed cell death called apoptosis, and immunity, can also induce autophagy. It is still a mystery how these specific signals turn on the autophagic machinery. What happens once autophagy is induced? Once the cell receives the appropriate signal, the autophagy-execution proteins trigger a cascade of reactions that result in membrane rearrangements to form a double-membrane- bound vesicle called an autophagosome (Fig. 1). Initially, an ‘isolation membrane’ forms, although its origin is still contro versial. The membrane surrounds the cytoplasmic contents to be degraded, and its edges fuse to form the autophagosome. This vesicle then fuses with a lysosome (or a vacuole in yeast), with the release of lysosomal digestive enzymes into the lumen of the resulting autolysosome. The sequestered cytoplasmic contents are degraded inside the autolysosome into free nucleotides, amino acids and fatty acids, which are reused by the cell to maintain macro- molecular synthesis and to fuel energy produc- tion. The nutrient recycling and housekeeping functions of autophagy promote cell survival, although in certain contexts autophagy may also promote cell death (Fig. 2, overleaf). Does autophagy also stop protein synthesis? No. On the contrary, one of its evolutionarily conserved functions, through protein re cycling, is to help maintain the synthesis of essential proteins when external nutrients are limited. Although certain stress stimuli that induce autophagy, such as starvation, turn off gen- eral protein synthesis, they also turn on the synthesis of specific stress-response proteins, including autophagy-execution proteins. So in this setting, the cell uses a coordinated strategy. To ensure that it has enough amino acids to synthesize the proteins that are essen- tial for its survival, general protein translation is shut down and autophagy is activated....
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This note was uploaded on 08/17/2009 for the course 26CB 880 taught by Professor Khan during the Spring '07 term at University of Cincinnati.

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Levine review - How is autophagy induced Autophagy occurs...

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