Chaperones in autophagy

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.

Figure 1. Chaperones in selective types of autophagy

Molecular chaperones participate in the recognition of cargo by three different autophagic pathways. Chaperone-mediated autophagy: where chaperones bind a KFERQ-like peptide motif in the substrate protein and deliver it to the surface of lysosomes; upon binding to the LAMP-2A receptor the substrate translocates across the membrane and is degraded. Endosomal microautophagy: where chaperones bind the same targeting motif in the soluble protein but deliver it to the surface of late endosomes; once there, internalization occurs through the formation of vesicles through invagination of the membrane and subsequent pinch-off. Chaperone-assisted selective autophagy: where chaperones bind substrate proteins organized in the form of aggregates and attract components of the autophagic machinery for the formation of an autophagosome around the aggregate. Degradation occurs upon fusion of the autophagosome with the lysosome.

Figure 2. Comparison of the different types of autophagy that require participation of molecular chaperones

The three autophagic pathways in which participation of chaperones have been described until date differ in the compartment in which cargo sequestration/degradation takes place, type of substrates, markers for substrate targeting and the need for substrate unfolding. They all share the same chaperone (hsc70) that binds directly to the substrates but to different components of the autophagic machinery.

Figure 3. Chaperones determine the fate of intracellular proteins

This scheme depicts some of the functions of chaperones in the regulation of proteostasis. Molecular chaperones participate in folding, aggregation, refolding and degradation of proteins through autophagic and non-autophagic pathways.