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Molecular and Cellular Biology, September 2008, p. 5747-5763, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.02070-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Chaperone-Mediated Autophagy Receptor Organizes in Dynamic Protein Complexes at the Lysosomal Membrane {triangledown} ,{dagger}

Urmi Bandyopadhyay,1 Susmita Kaushik,1 Lyuba Varticovski,2 and Ana Maria Cuervo1*

Departments of Developmental and Molecular Biology and of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461,1 Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 208922

Received 18 November 2007/ Returned for modification 26 December 2007/ Accepted 2 July 2008

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.

* Corresponding author. Mailing address: Department of Developmental and Molecular Biology, Ullmann Building Room 611D, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-2689. Fax: (718) 430-8975. E-mail: amcuervo{at}aecom.yu.edu

{triangledown} Published ahead of print on 21 July 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2008, p. 5747-5763, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.02070-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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