Chaperone-mediated autophagy at a glance

Abstract

Chaperone-mediated autophagy (CMA) is an intracellular catabolic pathway that mediates the degradation of a selective subset of cytosolic proteins in lysosomes (Dice, 2007;Cuervo, 2010;Kon and Cuervo, 2010;Orenstein and Cuervo, 2010). The term autophagy (or selfeating) is broadly used to designate the lysosomal delivery and degradation of intracellular components (Mizushima et al., 2008;Mizushima and Levine, 2010;Yang and Klionsky, 2010). Various types of autophagy coexist in almost all cells, and they can be differentiated by the mechanisms that mediate the delivery of cargo (the substrates to be degraded) to lysosomes. Macroautophagy and microautophagy are variants of the autophagic process, in which entire regions of cytosol (in 'bulk' autophagy) or selective cytosolic components (organelles, protein complexes, protein aggregates, pathogens, etc.) are sequestered in vesicular compartments. Lysosomal enzymes can gain access to the enclosed cargo through direct fusion of the vesicles with lysosomes (in macroautophagy), or by internalization of cargo-containing vesicles that form at the lysosomal membrane (in microautophagy). A third form of autophagy, solely dedicated to degradation of soluble proteins can also be detected in most cell types in mammals. This autophagic process, known as chaperone-mediated autophagy, differs from the other forms of autophagy in both the way in which cargo proteins are recognized for lysosomal delivery and the way in which these proteins reach the lysosomal lumen (Dice, 2007;Cuervo, 2010). In this article and the accompanying poster, we summarize the main steps involved in degradation of cytosolic proteins by CMA, the essential components of this pathway both in the cytosol and at the lysosomal membrane and the basis for the regulation of this autophagic process. We also include a synopsis of the described physiological functions of CMA and some (See poster insert) Degradation by the lysosomal proteases CMA is a selective form of autophagy by which single soluble proteins are directed one-by-one to lysosomes for degradation.The steps in CMA are:Validated CMA substrates

Structure of Transmembrane Domain of Lysosome-associated Membrane Protein Type 2a (LAMP-2A) Reveals Key Features for Substrate Specificity in Chaperone-mediated Autophagy

“…This coupling between Hsc70 binding of substrate and their simultaneous interaction with the cytosolic tail of LAMP-2A is key in providing specificity in the CMA process. In addition to the above role, Hsc70 binding to the LAMP-2A cytosolic tail ensures there is a population of this chaperone around the receptor to prevent aggregation as well as to promote the unfolding of protein substrates that is required for translocation (46,52,81).…”

Autophagy: for better or for worse

“…Mediated by heat shock cognate 70 and its co-chaperones, these proteins are directly targeted to the lysosomes. Degradation then occurs upon interaction with and internalization through the lysosomal receptor lysosomal-associated membrane protein 2 (LAMP-2A) [3]. During microautophagy, the lysosomal membrane invaginates to engulf portions of the cytoplasm,which are broken down once they are entirely enclosed.…”

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

“…Autophagic cargoes that are delivered to the lysosome are digested by lysosomal hydrolases to their basic components (i.e., amino acids and fatty acids), which are reutilized for anabolic pathways and energy production (112,138). In addition to macroautophagy, two additional subtypes of autophagy (i.e., microautophagy and chaperone-mediated autophagy) have been described (71,148,152) (see Fig. 1).…”