Abstract

All types of autophagy fulfill two important functions in mammalian cells, serving both as an alternative source of energy, when nutrients are scarce, and as an efficient mechanism for the removal of any intracellular damaged structures. In this talk, I will focus on a selective form of autophagy, known as chaperone-mediated autophagy (CMA) and the connections between this pathway and cellular quality control. CMA mediates selective targeting of soluble cytosolic proteins to lysosomes for their degradation. CMA is active in most cell types in mammalians but its activity varies depending on cellular conditions. Maximal activation of this pathway occurs during stress or in conditions leading to increased amount of misfolded/damaged proteins. Degradation via this pathway requires a set of cytosolic and lysosomal chaperones and a receptor protein at the lysosomal membrane, the lysosome-associated membrane protein type 2A (LAMP-2A). The limiting step of this type of autophagy is the binding of substrates to LAMP -2A. We have found that changes in the levels and organization of LAMP -2A at the lysosomal membrane underlie the molecular basis for the regulation of CMA . Two lysosomal chaperones, hsc70 and hsp90, are critical regulators of the higher order organization of LAMP -2A and the assembly of the translocation complex. . In recent years, the better molecular characterization of CMA has considerably advanced our understanding of the physiological role of this pathway and the consequences of its malfunctioning in the pathogenesis of detrimental human pathologies, such as cancer, neurodegenerative and metabolic diseases. In this talk, I will describe some of the recent findings on the interplay between pathogenic proteins and CMA . We are addressing this interaction as a two-side relationship: 1) the contribution of CMA to the removal of pathogenic proteins and 2) the effect that pathogenic proteins can exert on CMA activity. Lastly, I will comment on the functional decline of CMA with age and the reasons behind this decline.