Cathepsin A regulates chaperone-mediated autophagy through cleavage of the lysosomal receptor.
Protective protein/cathepsin A (PPCA) has a serine carboxypeptidase activity of unknown physiological function. We now demonstrate that this protease activity triggers the degradation of the lysosome-associated membrane protein type 2a (lamp2a), a receptor for chaperone-mediated autophagy (CMA). Degradation of lamp2a is important because its level in the lysosomal membrane is a rate-limiting step of CMA. Cells defective in PPCA show reduced rates of lamp2a degradation, higher levels of lamp2a and higher rates of CMA. Restoration of PPCA protease activity increases rates of lamp2a degradation, reduces levels of lysosomal lamp2a and reduces rates of CMA. PPCA associates with lamp2a on the lysosomal membrane and cleaves lamp2a near the boundary between the luminal and transmembrane domains. In addition to the well-studied role of PPCA in targeting and protecting two lysosomal glycosidases, we have defined a role for the proteolytic activity of this multifunctional protein.
Cuervo
Ana Maria
AM
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. amcuervo@aecom.yu.edu
Mann
Linda
L
Bonten
Erik J
EJ
d'Azzo
Alessandra
A
Dice
J Fred
JF
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001343:Autophagy; D016026:Bone Marrow Transplantation / Q000502:physiology; D002268:Carboxypeptidases / Q000737:chemistry / Q000378:metabolism*; D043402:Cathepsin A; D003600:Cytosol / Q000201:enzymology; D007425:Intracellular Membranes / Q000201:enzymology; D007700:Kinetics; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000502:physiology*; D008969:Molecular Sequence Data; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism
D015703:Antigens, CD; D051907:Lysosomal Membrane Proteins; D018832:Molecular Chaperones; D002268:Carboxypeptidases; D043402:Cathepsin A; D012697:Serine Endopeptidases