The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane.
Chaperone-mediated autophagy (CMA) is a selective type of autophagy by which specific cytosolic proteins are sent to lysosomes for degradation. Substrate proteins bind to the lysosomal membrane through the lysosome-associated membrane protein type 2A (LAMP-2A), one of the three splice variants of the lamp2 gene, and this binding is limiting for their degradation via CMA. However, the mechanisms of substrate binding and uptake remain unknown. We report here that LAMP-2A organizes at the lysosomal membrane into protein complexes of different sizes. The assembly and disassembly of these complexes are a very dynamic process directly related to CMA activity. Substrate proteins only bind to monomeric LAMP-2A, while the efficient translocation of substrates requires the formation of a particular high-molecular-weight LAMP-2A complex. The two major chaperones related to CMA, hsc70 and hsp90, play critical roles in the functional dynamics of the LAMP-2A complexes at the lysosomal membrane. Thus, we have identified a novel function for hsc70 in the disassembly of LAMP-2A from these complexes, whereas the presence of lysosome-associated hsp90 is essential to preserve the stability of LAMP-2A at the lysosomal membrane.
Bandyopadhyay
Urmi
U
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Kaushik
Susmita
S
Varticovski
Lyuba
L
Cuervo
Ana Maria
AM
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000737:chemistry / Q000378:metabolism*; D052119:Lysosomal-Associated Membrane Protein 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008970:Molecular Weight; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D050883:HSC70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D046912:Multiprotein Complexes; D020033:Protein Isoforms