New Insights into the Mechanisms of Chaperon-Mediated Autophagy and Implications for Kidney Diseases

Yuan, Zhen; Wang, Shuyuan; Tan, Xiaoyue; Wang, Dekun

doi:10.3390/cells11030406

Cited by 10 publications

(4 citation statements)

References 109 publications

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“…Hsp70s could recognize and bind a KFERQ-like pentapeptide motif in the substrate proteins, making them the key proteins required for chaperone-mediated autophagy (CMA) to deliver cargo to lysosomes. CMA degrades target soluble proteins in a selective manner and is the predominant form of autophagy in the tubular system ( 32 , 33 ). Hsp70s would regulate autophagic flux through the ubiquitin-mediated proteasome system and also the autophagosome–lysosome fusion system ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

Wang

Hao

et al. 2022

Front. Endocrinol.

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Pyruvate kinase M2 (PKM2), as the terminal and last rate-limiting enzyme of the glycolytic pathway, is an ideal enzyme for regulating metabolic phenotype. PKM2 tetramer activation has shown a protective role against diabetic kidney disease (DKD). However, the molecular mechanisms involved in diabetic tubular have not been investigated so far. In this study, we performed transcriptome gene expression profiling in human renal proximal tubular epithelial cell line (HK-2 cells) treated with 25 mM high D-glucose (HG) for 7 days before the addition of 10 μM TEPP-46, an activator of PKM2 tetramerization, for a further 1 day in the presence of HG. Afterwards, we analyzed the differentially expressed (DE) genes and investigated gene relationships based on weighted gene co-expression network analysis. The results showed that 2,902 DE genes were identified (adjusted P-value ≤ 0.05), where 2,509 DE genes (86.46%) were co-expressed in the key module. Four extremely downregulated DE genes (HSPA8, HSPA2, HSPA1B, and ARRB1) and three extremely upregulated DE genes (GADD45A, IGFBP3, and SIAH1) enriched in the downregulated endocytosis (hsa04144) and upregulated p53 signaling pathway (hsa04115), respectively, were validated by qRT-PCR experiments. The qRT-PCR results showed that the relative expression levels of HSPA8 [adjusted P-value = 4.45 × 10-34 and log2(FC) = -1.12], HSPA2 [adjusted P-value = 6.09 × 10-14 and log2(FC) = -1.27], HSPA1B [adjusted P-value = 1.14 × 10-11 and log2(FC) = -1.02], and ARRB1 [adjusted P-value = 2.60 × 10-5 and log2(FC) = -1.13] were significantly different (P-value < 0.05) from the case group to the control group. Furthermore, the interactions and predicted microRNAs of the key genes (HSPA8, HSPA2, HSPA1B, and ARRB1) were visualized in networks. This study identified the key candidate transcriptomic biomarkers and biological pathways in hyperglycemic HK-2 cells responding to the PKM2 activator TEPP-46 that can highlight a possibility of PKM2 tetramerization reshaping the interplay among endocytic trafficking through the versatile networks of Hsp70s and rewiring the crosstalk between EGFR signal transduction circuits and metabolic stress to promote resilience, which will be valuable for further research on PKM2 in DKD.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

Wang

Hao

et al. 2022

Front. Endocrinol.

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“…Since oxidative stress is commonly involved in various chronic diseases, Nrf2 could be a therapeutic target for these chronic diseases [ 60 ]. Moreover, CMA failure has also been reported in patients with chronic liver and kidney diseases [ 61 , 62 ]. It is expected that D-cysteine can be used as a novel Nrf2 and CMA activator selective for the cerebellum, liver, and kidneys via hydrogen sulfide production.…”

Section: Discussionmentioning

confidence: 99%

D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation

Ueda

Ohta

Konno

et al. 2022

Cells

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Chaperone-mediated autophagy (CMA) is a pathway in the autophagy-lysosome protein degradation system. CMA impairment has been implicated to play a role in spinocerebellar ataxia (SCA) pathogenesis. D-cysteine is metabolized by D-amino acid oxidase (DAO), leading to hydrogen sulfide generation in the cerebellum. Although D-cysteine alleviates the disease phenotypes in SCA-model mice, it remains unknown how hydrogen sulfide derived from D-cysteine exerts this effect. In the present study, we investigated the effects of D-cysteine and hydrogen sulfide on CMA activity using a CMA activity marker that we have established. D-cysteine activated CMA in Purkinje cells (PCs) of primary cerebellar cultures where DAO was expressed, while it failed to activate CMA in DAO-deficient AD293 cells. In contrast, Na2S, a hydrogen sulfide donor, activated CMA in both PCs and AD293 cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is known to be activated by hydrogen sulfide and regulate CMA activity. An Nrf2 inhibitor, ML385, prevented CMA activation triggered by D-cysteine and Na2S. Additionally, long-term treatment with D-cysteine increased the amounts of Nrf2 and LAMP2A, a CMA-related protein, in the mouse cerebellum. These findings suggest that hydrogen sulfide derived from D-cysteine enhances CMA activity via Nrf2 activation.

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“…On the other hand, dysfunction of CMA as a consequence of some diseases can aggravate the pathology. That is the case in the involvement of suppressed CMA activity in several pathologic conditions in the kidney [106]. The accumulation of CMA substrates by impaired CMA in the renal cortex during acute diabetes mellitus might also be associated with the development of diabetic-induced renal hypertrophy [106,107].…”

Section: Aging-associated Diseases and Other Pathologiesmentioning

confidence: 98%

The Role of Chaperone-Mediated Autophagy in Tissue Homeostasis and Disease Pathogenesis

Valdor,

Martinez-Vicente

2024

Biomedicines

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Chaperone-mediated autophagy (CMA) is a selective proteolytic pathway in the lysosomes. Proteins are recognized one by one through the detection of a KFERQ motif or, at least, a KFERQ-like motif, by a heat shock cognate protein 70 (Hsc70), a molecular chaperone. CMA substrates are recognized and delivered to a lysosomal CMA receptor, lysosome-associated membrane protein 2A (LAMP-2A), the only limiting component of this pathway, and transported to the lysosomal lumen with the help of another resident chaperone HSp90. Since approximately 75% of proteins are reported to have canonical, phosphorylation-generated, or acetylation-generated KFERQ motifs, CMA maintains intracellular protein homeostasis and regulates specific functions in the cells in different tissues. CMA also regulates physiologic functions in different organs, and is then implicated in disease pathogenesis related to aging, cancer, and the central nervous and immune systems. In this minireview, we have summarized the most important findings on the role of CMA in tissue homeostasis and disease pathogenesis, updating the recent advances for this Special Issue.

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New Insights into the Mechanisms of Chaperon-Mediated Autophagy and Implications for Kidney Diseases

Cited by 10 publications

References 109 publications

Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

Transcriptomic signatures responding to PKM2 activator TEPP-46 in the hyperglycemic human renal proximal epithelial tubular cells

D-Cysteine Activates Chaperone-Mediated Autophagy in Cerebellar Purkinje Cells via the Generation of Hydrogen Sulfide and Nrf2 Activation

The Role of Chaperone-Mediated Autophagy in Tissue Homeostasis and Disease Pathogenesis

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