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.