Abstract
Chaperone-mediated autophagy (CMA) is a separate type of lysosomal proteolysis, characterized by its selectivity of substrate proteins and direct translocation into lysosomes. Recent studies have declared the involvement of CMA in a variety of physiologic and pathologic situations involving the kidney, and it has emerged as a potential target for the treatment of kidney diseases. The role of CMA in kidney diseases is context-dependent and appears reciprocally with macroautophagy. Among the renal resident cells, the proximal tubule exhibits a high basal level of CMA activity, and restoration of CMA alleviates the aging-related tubular alternations. The level of CMA is up-regulated under conditions of oxidative stress, such as in acute kidney injury, while it is declined in chronic kidney disease and aging-related kidney diseases, leading to the accumulation of oxidized substrates. Suppressed CMA leads to the kidney hypertrophy in diabetes mellitus, and the increase of CMA contributes to the progress and chemoresistance in renal cell carcinoma. With the progress on the understanding of the cellular functions and uncovering the clinical scenario, the application of targeting CMA in the treatment of kidney diseases is expected.
Highlights
Autophagy plays an important role in balancing protein synthesis and degradation, maintaining proper cellular homeostasis [1]
We focus on the progress with regard to the pathogenesis and implications of chaperone-mediated autophagy (CMA)
Besides the two major chaperones involved in CMA, HSC70 and heat shock protein 90 (HSP90), there are a subset of co-chaperones which are responsible for this process, including HSP40, Bcl-2 associate athanogene 2 (BAG-1), hsc70-hsp90 organizing protein (HOP), and hsc70interacting protein (HIP) [36]
Summary
Autophagy plays an important role in balancing protein synthesis and degradation, maintaining proper cellular homeostasis [1]. CMA-defective cells are more vulnerable to different stressors [6] This compensation tends to decrease with stress or aging [7]. Both CMA and macroautophagy can be activated by starvation, but their sequential activations play different roles in response to stressors [8]. Proteins targeted for degradation by CMA cross the lysosomal membrane one-by-one through a protein translocation system with the assistance of cytosolic chaperones such as HSC70, which recognizes and binds a KFERQ-like pentapeptide motif in the substrate protein [9,10]. Almost all mammalian cell types show a basal CMA; liver and kidney have the highest percentage of protein containing a KFERQ-motif [12]. Glomerular podocytes have a high level of basal macroautophagy, and CMA is the predominant form of autophagy in the tubular system [13]. We focus on the progress with regard to the pathogenesis and implications of CMA in the kidney diseases
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