Chaperone-mediated autophagy (CMA) was the first studied process that indicated that degradation of intracellular components by the lysosome can be selective — a concept that is now well accepted for other forms of autophagy. Lysosomes can degrade cellular cytosol in a nonspecific manner but can also discriminate what to target for degradation with the involvement of a degradation tag, a chaperone and a sophisticated mechanism to make the selected proteins cross the lysosomal membrane through a dedicated translocation complex. Recent studies modulating CMA activity in vivo using transgenic mouse models have demonstrated that selectivity confers on CMA the ability to participate in the regulation of multiple cellular functions. Timely degradation of specific cellular proteins by CMA modulates, for example, glucose and lipid metabolism, DNA repair, cellular reprograming and the cellular response to stress. These findings expand the physiological relevance of CMA beyond its originally identified role in protein quality control and reveal that CMA failure with age may aggravate diseases, such as ageing-associated neurodegeneration and cancer.

The coming of age of chaperone-mediated autophagy.

Antioxidant properties and potential mechanisms of hydrolyzed proteins and peptides from cereals.

Nowadays, heat shock protein 90 (Hsp90), a highly conserved molecular chaperone, has become the target of antitumor drugs as a result of its close relationship with the occurrence and development, biological behavior, and prognosis of a tumor. Autophagy has attracted big attention recently for its paradoxical roles in cell survival and cell death, especially in the pathogenesis and treatment of cancer. Moreover, it has been verified that Hsp90 plays a role in autophagy via regulating the stability and activity of signaling proteins, and some Hsp90 inhibitors can induce autophagy. However, the underlying mechanisms for these important processes have not been clarified so far. In this study, we focus on the roles of Hsp90 in the regulation of autophagy, such as toll-like receptor (TLR)-mediated autophagy, Ulk1-mediated mitophagy, and chaperone-mediated autophagy (CMA). The roles of Hsp90 inhibitors in cancer therapy will also be elucidated.

Hsp90 regulates autophagy and plays a role in cancer therapy.

Autophagy is a catabolic process by which eukaryotic cells eliminate cytosolic materials through vacuole-mediated sequestration and subsequent delivery to lysosomes for degradation, thus maintaining cellular homeostasis and the integrity of organelles. Autophagy has emerged as playing a critical role in the regulation of liver physiology and the balancing of liver metabolism. Conversely, numerous recent studies have indicated that autophagy may disease-dependently participate in the pathogenesis of liver diseases, such as liver hepatitis, steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma. This review summarizes the current knowledge on the functions of autophagy in hepatic metabolism and the contribution of autophagy to the pathophysiology of liver-related diseases. Moreover, the impacts of autophagy modulation on the amelioration of the development and progression of liver diseases are also discussed.

https://www.mdpi.com/1422-0067/20/2/300/pdf

Diverse Functions of Autophagy in Liver Physiology and Liver Diseases.

Chaperone Mediated Autophagy (CMA) is a lysosomal-dependent protein degradation pathway. At least 30% of cytosolic proteins can be degraded by this process. The two major proteins players of CMA are LAMP-2A and Hsc70. Whereas LAMP-2A works as receptor for protein substrates at the lysosomal membrane, Hsc70 specifically binds protein targets and takes them for CMA degradation. Because of the broad spectrum of proteins able to be degraded by CMA, this pathway has been involved in physiological and pathological processes like lipid and carbohydrate metabolism, and neurodegenerative diseases, respectively. Both, CMA, and the mentioned processes, are affected by aging and by inadequate nutritional habits like high fat diet or high carbohydrate diet. Little is known regarding to CMA being considered as a common regulation factor that links metabolism with neurodegenerative disorders. This review summarizes what is known about CMA, focusing the attention in its molecular mechanism, its role in protein, lipid and carbohydrate metabolism. In addition, the review will discuss how CMA could be a link to connect protein, lipids and carbohydrate metabolism with neurodegenerative diseases. Furthermore, it will be discussed how aging and inadequate nutritional habits, can have an impact at both, CMA activity and neurodegenerative disorders.

/pdf/chaperone-mediated-autophagy-in-the-crosstalk-of-5g39wnf129.pdf

Chaperone Mediated Autophagy in the Crosstalk of Neurodegenerative Diseases and Metabolic Disorders.

RVF (Arg-Val-Phe), a peptide derived from wheat germ, shows antioxidant properties. Here, the neuroprotective efficacies of RVF were investigated in human neuroblastoma cells (SH-SY5Y) that were pretreated with RVF (150-250 μM, 4 h) and exposed to H2O2 (200 μM). RVF increased viable cell numbers by 37 % and reduced the release of lactate dehydrogenase. Pretreatment with RVF also inhibited H2O2-induced accumulation of reactive oxygen species and maintained the mitochondrial transmembrane potential as well as preventing intracellular Ca(2+) dysregulation during H2O2 exposure. Furthermore, pretreatment with RVF increased the Bcl-2/Bax ratio and blocked cleavage poly(ADP-ribose) polymerase by inhibiting caspase-3 activation, thus decreasing apoptosis.

Protective effects of a wheat germ peptide (RVF) against H2O2-induced oxidative stress in human neuroblastoma cells

Oxidative stress has been implicated in both normal aging and various neurodegenerative disorders and it may be a major cause of neuronal death. Chaperone-mediated autophagy (CMA) targets selective cytoplasmic proteins for degradation by lysosomes and protects neurons against various extracellular stimuli including oxidative stress. MEF2A (myocyte enhancer factor 2A), a key transcription factor, protects primary neurons from oxidative stress-induced cell damage. However, the precise mechanisms of how the protein stability and the transcriptional activity of MEF2A are regulated under oxidative stress remain unknown. In this study, we report that MEF2A is physiologically degraded through the CMA pathway. In pathological conditions, mild oxidative stress (200 μM H2O2) enhances the degradation of MEF2A as well as its activity, whereas excessive oxidative stress (> 400 μM H2O2) disrupts its degradation process and leads to the accumulation of nonfunctional MEF2A. Under excessive oxidative stress, an N-terminal HDAC4 (histone deacetylase 4) cleavage product (HDAC4-NT), is significantly induced by lysosomal serine proteases released from ruptured lysosomes in a PRKACA (protein kinase, cAMP-dependent, catalytic, α)-independent manner. The production of HDAC4-NT, as a MEF2 repressor, may account for the reduced DNA-binding and transcriptional activity of MEF2A. Our work provides reliable evidence for the first time that MEF2A is targeted to lysosomes for CMA degradation; oxidative stress-induced lysosome destabilization leads to the disruption of MEF2A degradation as well as the dysregulation of its function. These findings may shed light on the underlying mechanisms of pathogenic processes of neuronal damage in various neurodegenerative-related diseases.

https://www.tandfonline.com/doi/pdf/10.4161/auto.28477

Disruption of chaperone-mediated autophagy-dependent degradation of MEF2A by oxidative stress-induced lysosome destabilization.

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Protective effects of a wheat germ peptide (RVF) against H2O2-induced oxidative stress in human neuroblastoma cells

Disruption of chaperone-mediated autophagy-dependent degradation of MEF2A by oxidative stress-induced lysosome destabilization.