Chapter category: Apoptosis
Chaperone-Mediated Autophagy
Autophagy
Edited by: Daniel KlionskyISBN: 1-58706-203-8
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Chapter authors:
J. Fred Dice, Patrick F. Finn, Amy E. Majeski, Nicholas T. Mesires and Ana Maria Cuervo
Chaperone-mediated autophagy (Cma) is responsible for the degradation of 30% of cytosolic proteins from fibroblasts, hepatocytes and many other cell types during prolonged starvation. All substrate proteins for this pathway of proteolysis contain a compositional peptide motif related to KFERQ. Isolated lysosomes carry out Cma, and these preparations demonstrate a requirement for a molecular chaperone, the heat shock cognate protein of 73 kDa (hsc73) and ATP for optimal activity. Substrate proteins bind to a receptor in the lysosomal membrane, the lysosome-associated membrane protein type 2a (lamp2a). After binding to lamp2a, the substrate protein is unfolded probably by a group of molecular chaperones still associated with the substrate-lamp2a complex. An intralysosomal form of hsc73 (ly-hsc73) is required for entry of the substrate protein into the lysosomal matrix. Lamp2a in the lysosomal membrane and ly-hsc73 are rate-limiting components of Cma. The amount of lamp2a in the lysosomal membrane can be increased in two ways; its degradation rate can be decreased and a fraction of the protein in the lysosomal matrix can be reinserted into the lysosomal membrane. Lamp2a is found in the lysosomal membrane as a homomultimer, but whether or not this multimerization is regulated is unclear. The intracellular signals that activate Cma are under investigation, and they seem distinct from activators of macroautophagy. Ketone bodies that accumulate in prolonged starvation activate Cma. Aging is accompanied by reduced activity of Cma, and the resulting reduced protein degradation may lead to the accumulation of damaged proteins. Three specific examples of substrates for Cma are discussed.
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