Consequences of the selective blockage of chaperone-mediated autophagy

doi:10.1073/pnas.0507436103

Consequences of the selective blockage of chaperone-mediated autophagy

Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann Building, Room 611, Bronx, NY 10461

Edited by Marilyn Gist Farquhar, University of California at San Diego School of Medicine, La Jolla, CA, and approved February 22, 2006 (received for review August 25, 2005)

Abstract

Chaperone-mediated autophagy (CMA) is a selective pathway for the degradation of cytosolic proteins in lysosomes. CMA declines with age because of a decrease in the levels of lysosome-associated membrane protein (LAMP) type 2A, a lysosomal receptor for this pathway. We have selectively blocked the expression of LAMP-2A in mouse fibroblasts in culture and analyzed the cellular consequences of reduced CMA activity. CMA-defective cells maintain normal rates of long-lived protein degradation by up-regulating macroautophagy, the major form of autophagy. Constitutive up-regulation of macroautophagy is unable, however, to compensate for all CMA functions. Thus, CMA-defective cells are more sensitive to stressors, suggesting that, although protein turnover is maintained, the selectivity of CMA is necessary as part of the cellular response to stress. Our results also denote the existence of cross-talk among different forms of autophagy.

Footnotes

*To whom correspondence should be addressed. E-mail: amcuervo{at}aecom.yu.edu
Author contributions: A.M.C. designed research; A.C.M., S.K., G.S., and R.K. performed research; A.C.M., S.K., G.S., R.K., and A.M.C. analyzed data; and A.M.C. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

CMA,

chaperone-mediated autophagy;

LAMP,

lysosome-associated membrane protein;

LC3,

microtubule-associated protein 1 light chain 3;

RNAi,

RNA interference;

3MA,

3-methyladenine.