Chaperone-mediated autophagy: a unique way to enter the lysosome world

Abstract

All cellular proteins undergo continuous synthesis and degradation. This permanent renewal is necessary to maintain a functional proteome and to allow rapid changes in levels of specific proteins with regulatory purposes. Although for a long time lysosomes were considered unable to contribute to the selective degradation of individual proteins, the discovery of chaperone-mediated autophagy (CMA) changed this notion. Here, we review the characteristics that set CMA apart from other types of lysosomal degradation and the subset of molecules that confer cells the capability to identify individual cytosolic proteins and direct them across the lysosomal membrane for degradation.

Figure 1

Steps and regulation of CMA. Steps: (a) Recognition of substrate proteins by hsc70/cochaperones; (b) binding of substrate-chaperone complex to LAMP-2A; (c) unfolding of the substrate; (d) LAMP-2A multimerization, substrate translocation and subsequent degradation; (e) disassembly of LAMP-2A multimer/translocon. Regulation of levels of LAMP-2A at the lysosomal membrane is attained through (1) de novo synthesis and (2) degradation in specialized microdomains at the lysosomal membrane.

Figure 2

Functions of CMA. a) By degrading no longer needed proteins during nutrient deprivation, CMA provides amino acids for the synthesis of needed proteins and generates energy. b) By degrading damaged and prone-to-aggregate proteins, CMA is an essential component of the cellular quality control system. c) CMA also has specialized functions, depending on the substrate protein and cells/tissues involved. Some examples discussed in the text are listed.

Figure 3

Pathology of CMA. a) Top: CMA is primarily compromised in some neurodegenerative diseases due to direct blockage of the translocation machinery by the pathogenic proteins. Bottom: Upregulation of CMA activity in Huntington’s disease compensates for the blockage in other degradative pathways and has been utilized for artificial targeting of the toxic protein. b) Cancer cells depend on CMA to sustain cellular proliferation and tumor growth. Continuous CMA activation maintains glycolytic activity and reduces stress in cancer cells. c) CMA activity is compromised in disorders that compromise lysosomal function and in metabolic diseases such as those related to alterations in lipid metabolism and diabetes. CMA activity also decreases with age.

Figure I

Comparison of endosomal-microautophagy (e-MI) and chaperone-mediated autophagy (CMA)