Chaperone-Mediated Autophagy in the Kidney: The Road More Traveled

Abstract

Summary Chaperone-mediated autophagy (CMA) is a lysosomal proteolytic pathway in which cytosolic substrate proteins contain specific chaperone recognition sequences required for degradation and are translocated directly across the lysosomal membrane for destruction. CMA proteolytic activity has a reciprocal relationship with macroautophagy: CMA is most active in cells in which macroautophagy is least active. Normal renal proximal tubular cells have low levels of macroautophagy, but high basal levels of CMA activity. CMA activity is regulated by starvation, growth factors, oxidative stress, lipids, aging, and retinoic acid signaling. The physiological consequences of changes in CMA activity depend on the substrate proteins present in a given cell type. In the proximal tubule, increased CMA results from protein or calorie starvation and from oxidative stress. Overactivity of CMA can be associated with tubular lysosomal pathology and certain cancers. Reduced CMA activity contributes to protein accumulation in renal tubular hypertrophy, but may contribute to oxidative tissue damage in diabetes and aging. Although there are more questions than answers about the role of high basal CMA activity, this remarkable feature of tubular protein metabolism appears to influence a variety of chronic diseases.

Chaperone-mediated autophagy regulates proliferation by targeting RND3 in gastric cancer

“…In this study, we examined the expression of LAMP2A in ten kinds of tumors, and found that LAMP2A was significantly upregulated in 8 kinds of human tumors, including lung cancer, breast cancer and gastric cancer, whereas, no significant increase was noticed in hepatic cell carcinoma and renal clear cell carcinoma, as its expression in normal liver cell and renal tubular cell was also very high. This is consistent with a previous finding, 27 supporting the notion that CMA is required for hepatic metabolism 24 and for proteostasis in renal tubular cells. 27 Nevertheless, our results strongly suggest that high CMA activity is a hallmark of malignancies.…”

“…3E), among which GAPDH, and PKM are well characterized CMA substrates, HSPA8 is the classic CMA chaperone, and PARK7/DJ-1 has been predicted to be a CMA substrate. 27 These proteins may help us to better understand the mechanisms through which CMA can regulate a range of biological pathways. We thoroughly examined our interactomic results, and found that RND3 was selected by KEGG analysis as a key regulator of the cytoskeleton, and its antiproliferative action has also been well characterized.…”

Autophagy in renal diseases

“…This is determined by its degradation by two proteases, a metalloprotease that cleaves the protein inside the lysosomal membrane and cathepsin A, which cleaves the intralysosomal portion of the protein. To a lesser extent, LAMP-2A levels are also determined by synthesis [17]. Ageing leads to less stable LAMP-2A, resulting in lower levels of CMA activity [16].…”

“…In cancer cells, CMA has been shown to be upregulated [20]. There is a functional reciprocal crosstalk between CMA and macroautophagy, as CMA is most active in cells in which macroautophagy is least active [17]. Inhibiting either one of these processes leads to upregulation of the other, thus providing a constant baseline autophagy level [6].…”

“…In the mature tubule, CMA is the predominant form of autophagy in the basal state [17]. Autophagy induction in tubular cells, especially in proximal tubular cells, plays an important role in protecting cells from stress as proteinuria-induced apoptosis and ischemic AKI, as shown in both in vitro and in vivo experimental models [5].…”