Chaperone-mediated autophagy in protein quality control
Section snippets
Introduction to selective autophagy
Cells assure the renewal of their constituent proteins through a continuous process of synthesis and degradation that also allows for rapid modulation of the levels of specific proteins to accommodate to the changing extracellular environment [1]. Intracellular protein degradation is also essential for cellular quality control to eliminate damaged or altered proteins, thus preventing the toxicity associated with their accumulation inside cells. Two major proteolytic systems exert this cleaning
Molecular characteristic of CMA
Selectivity in selection of CMA cargo is attained through the interaction of a cytosolic chaperone, the heat shock-cognate chaperone of 70 kDa, hsc70, with a specific region in the amino acid sequence of the proteins destined for degradation. All CMA substrates contain in their sequence a consensus motif, biochemically related to the pentapeptide KFERQ that when exposed (i.e. during protein misfolding or disassembly of protein complexes), is recognized by hsc70 and in a process modulated by the
Physiological role of CMA: what crosses the lysosomal membrane and when
Sequence analysis has revealed that about 30% of cytosolic proteins contain in their sequence putative motifs for CMA targeting. Immunoprecipitation studies with an antibody that recognizes the structural characteristics of the CMA-tageting motif are in agreement with this estimation. The approximately fifty already validated CMA substrates fall in a broad range of protein categories, including, among others, glycolytic enzymes (GAPDH, aldolase, PGM) [17], transcription factors (c-fos, Pax,
CMA dysfunction in proteinopathies
Dysfunction of CMA activity has been described in a growing number of pathologies (reviewed in [6, 35, 36]). Because of the interest for this focused issue, we describe here those pathologies related to alterations in protein homeostasis also known as proteinopathies or protein conformational disorders (Figure 2).
The first connection between proteotoxicity and CMA in the context of disease was established with a type of nephropathy induced by exposure to gasoline derivatives that upon
Proteotoxicity associated with aging and CMA
Accumulation of protein damage is a common feature of most tissues in aging organisms. Compromised quality control with age contributes to altered protein homeostasis [42, 43]. Age-dependent changes in the lysosomal system and the subsequent decline in autophagic activity were identified even before the molecular mechanisms that govern the different autophagic pathways were fully understood [42, 43]. Both macroautophagy and CMA activity decrease with age in most organs in aging mammals. This
Concluding remarks
Selectivity in protein removal as part of cellular quality control has been traditionally attributed solely to the ubiquitin-proteasome system. However, the precise coordinated action of cytosolic chaperones and different protein components at the lysosomal membrane allows lysosomes to perform similar selective removal of proteins via CMA. This autophagic pathway reveals itself as an important component of the cellular response to those stressors damaging the soluble cellular proteome. The
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors want to express their profound appreciation for the late Fred Dice (‘Paulo’) for his pioneering work on this pathway and for the great influence that he and his work have always had, and will continue to have, in this field. We thank Ms. Samantha Orenstein for critically reading the manuscript. Work in our laboratory is supported by NIH grants from NIA (AG021904, AG031782), NIDKK (DK041918), NINDS (NS038370), a Glenn Foundation Award and a Hirsch/Weill-Caulier Career Scientist
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