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  • The EMBO Journal (2003) 22, 47 - 59
  • doi:10.1093/emboj/cdg002

Cathepsin A regulates chaperone-mediated autophagy through cleavage of the lysosomal receptor

Ana Maria Cuervo1, Linda Mann2, Erik J. Bonten2, Alessandra d'Azzo2 and J. Fred Dice3

  1. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
  2. Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA
  3. Department of Physiology, Tufts University School of Medicine, Boston, MA 02111, USA

Correspondence to:

Ana Maria Cuervo, E-mail: amcuervo@aecom.yu.edu

Received 4 June 2002; Accepted 31 October 2002; Revised 4 October 2002

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). Degrada tion 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.

  • Keywords:

    • autophagy,
    • galactosialidosis,
    • lysosomes,
    • proteases,
    • protein degradation