Chaperone-mediated autophagy.
Chaperone-mediated autophagy (CMA) is a lysosomal pathway of proteolysis that is responsible for the degradation of 30% of cytosolic proteins under conditions of prolonged nutrient deprivation. Molecular chaperones in the cytosol and in the lysosomal lumen stimulate this proteolytic pathway. The molecular chaperones in the cytosol unfold substrate proteins prior to their translocation across the lysosomal membrane, while the chaperone in the lysosomal lumen is probably required to pull the substrate protein across the lysosomal membrane. A critical component for CMA is a receptor in the lysosomal membrane, the lysosome-associated membrane protein (LAMP) type 2A. LAMP-2A levels in the lysosomal membrane can be increased by reduced degradation and/or redistribution from the lysosomal lumen to the lysosomal membrane. Recent results show that CMA is also activated by oxidative stress, and in this case LAMP-2A is increased due to transcriptional regulation. CMA can be reduced by inhibitors of glucose-6-phosphate dehydrogenase and of the heat shock protein of 90 kDa. Reduction of levels of LAMP-2A using RNAi strategies reduces CMA activity, but macroautophagy is activated as a result. The decrease in CMA causes cells to be more susceptibile to oxidative and other stresses. LAMP-2A in the lysosomal membrane can be sequestered into cholesterol-rich microdomains where it is inactive. When CMA is activated, LAMP-2A moves out of these domains. The reduced CMA in aging is due to reduced LAMP-2A in the lysosomal membrane. This reduction is caused by an age-related increased degradation of LAMP-2A and an age-related reduced ability of LAMP-2A to reinsert into the lysosomal membrane. These findings reveal a rich complexity of mechanisms to control CMA activity.
Dice
J Fred
JF
Department of Cellular and Molecular Physiology, Tufts University School of Medicine, Boston, MA 02111, USA. james.dice@tufts.edu
D001343:Autophagy / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology; D006360:Heat-Shock Proteins / Q000502:physiology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism; D008954:Models, Biological; D018832:Molecular Chaperones / Q000502:physiology*; D011506:Proteins / Q000502:physiology
D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D018832:Molecular Chaperones; D011506:Proteins