Elsevier

Pharmacological Research

Volume 66, Issue 6, December 2012, Pages 484-493
Pharmacological Research

Invited review
Chaperones in autophagy

https://doi.org/10.1016/j.phrs.2012.10.002Get rights and content

Abstract

Cells continuously turn over proteins through cycles of synthesis and degradation in order to maintain a functional proteome and to exert a tight control in the levels of regulatory proteins. Selective degradation of proteins was initially thought to be an exclusive function of the ubiquitin–proteasome system, however, over the years, the contribution of lysosomes to this selective degradation, through the process of autophagy, has become consolidated. In this context, molecular chaperones, classically associated with protein folding, unfolding and assembling have been revealed as important modulators of selectivity during the autophagic process. Here, we review this relatively new role of chaperones in mediating selective autophagy and comment on how alterations of this function can lead to human pathologies associated to proteotoxicity.

Section snippets

Introduction: selectivity in autophagy

Since its discovery in the mid-1950s, autophagy was considered a non-selective process by which whole regions of the cytosol were degraded “in bulk” inside lysosomes [1]. The idea of selectivity in degradation of proteins was not considered until later when the ubiquitin–proteasome system was identified and demonstrated to be capable of eliminating only a specific subset of proteins, those previously tagged with ubiquitin [2].

Although for a while selective degradation was solely linked to the

Concept

CMA degrades only those soluble cytosolic proteins that contain a targeting motif related to the pentapeptide KFERQ [4], [30]. This motif is recognized by a cytosolic chaperone, hsc70, which mediates the delivery of the substrate protein to the surface of the lysosome [30], [31]. CMA is upregulated in response to stressors, such as oxidative stress, hypoxia, starvation and exposure to toxic compounds [32], [33], [34], [35]. During prolonged starvation, by degrading no-longer needed proteins,

Microautophagy: hsc70-dependent selectivity

Traditionally, microautophagy has been described as a process that involves the entrapment of cytosol by invaginations of the lysosomal membrane and subsequent degradation of the cargo-containing vesicle after it pinches off from the lysosomal membrane [54]. In mammalian cells, of the three forms of autophagy, microautophagy has been the least studied, mainly due to the lack of information on the molecular components that participate in this process. In fact, in most early studies the

Macroautophagy: CASA

Added to the role of hsc70 in targeting of proteins for CMA and eMI described in previous sections, recent studies have revealed the contribution of this chaperone in the removal of aggregated proteins via macroautophagy in a process known as chaperone-assisted selective autophagy (CASA) [29].

Pathological implications of the contribution of chaperones to autophagy

As alluded to earlier, the selective degradation of proteins via autophagy, in the form of CMA, eMI or CASA, is critical to maintain proteostasis in normal physiological conditions [66]. In fact, when the activity of any of these pathways is compromised due to pathology and/or aging, cellular homeostasis is severely affected and the occurrence of proteotoxicity leads often to cellular malfunction and in many instances to cell death. In the initial stages of failure of one pathway, there is

Concluding remarks

The important role that chaperones play in modulating different forms of selective autophagy is just beginning to be recognized. Despite the need for additional dissection of the different steps and regulators that participate in the different types of autophagy dependent on chaperones, a series of common themes has started to be delineated. Thus, the hsp70 family of chaperones and in particular, the constitutive variant of this family hsc70, is shared by the three types of autophagy (Fig. 3),

Acknowledgments

Work in our laboratory is supported by the National Institute of Health grants from NIA and NINDS, the Beatrice and Roy Backus Foundation, the Rainwaters Foundation, a Hirsch/Weill-Caulier Career Scientist Award to AMC and the generous support of Robert and Renee Belfer.

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