Deficient Chaperone-Mediated Autophagy in Liver Leads to Metabolic Dysregulation

Schneider, Jaime L.; Suh, Yousin; Cuervo, Ana María

doi:10.1016/j.cmet.2014.06.009

Cited by 274 publications

(385 citation statements)

References 41 publications

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“…In this regard, we have examined the role of CMA. Our data do not suggest an accumulation of CMA substrates, 40 as would be expected with ablation of the LAMP2A isoform in lamp2 null mice), 28 which could conceivably be due to upregulation of alternate protein degradation mechanisms. Importantly, the levels of these substrates were not altered by the intermittent fasting regimen, suggesting that CMA is unlikely to be a significant contributor to the observed cardioprotective effects.…”

Section: Discussioncontrasting

confidence: 45%

“…40 This pathway has been shown to be activated in the myocardium by fasting, in vivo, and by oxidative stress. 41 To examine its role in intermittent-fasting induced cardioprotection, we assessed the abundance of candidate proteins that are known chaperonemediated autophagy substrates 40 in the myocardium, in these models. Interestingly, our data do not demonstrate any significant alteration in abundance of these proteins with intermittent fasting or Lamp2 ablation (which also results in loss of the LAMP2A isoform; 28 see Fig.…”

Section: Intermittent Fasting Modulates Oxidative Stress In the Myocamentioning

confidence: 99%

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Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

et al. 2015

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(2015) Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemiareperfusion injury, Autophagy, 11:9, 1537-1560, DOI: 10.1080/15548627.2015 Keywords: autophagy, fasting, ischemia-reperfusion, lysosome, myocardial infarctionAbbreviations: CMA, chaperone-mediated autophagy; CQ, chloroquine; GFP, green fluorescent protein; LAD, left anterior descending; LAMP2, lysosomal-associated membrane protein 2; MOI, multiplicity of infection; NRCMs, neonatal rat ventricular cardiac myocytes; q4D, quaque qutra die/every fourth day; qOD, quaque otra die/every other day; TFEB, transcription factor EB; MAP1LC3B (also abbreviated as LC3), microtubule-associated protein 1 light chain 3, isoform B; TTC, triphenyl tetrazolium chloride; LV, left ventricle; AAR, area at risk; WT, wild type.Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from invivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEBmediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fastinginduced autophagy in myocardial ischemia-reperfusion injury.

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Section: Discussioncontrasting

confidence: 45%

Section: Intermittent Fasting Modulates Oxidative Stress In the Myocamentioning

confidence: 99%

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

et al. 2015

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“…This lysosomal degradation occurred, in large part, through CMA, as genetic blockage of this pathway almost completely abolished lysosomal degradation of WT tau and led to its accumulation (Fig. 1a,b; GAPDH is shown as an example of a well‐characterized CMA substrate (Aniento et al ., 1993) known to accumulate intracellularly upon blockage of CMA (Schneider et al ., 2014)). Tau‐A152T displayed very similar degradation dynamics, although this mutation slightly reduced tau's rates of lysosomal degradation (20% inhibition) when compared with WT tau (Fig.…”

Section: Resultsmentioning

confidence: 99%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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“…Blockage of CMA in vitro and in vivo is compensated for by upregulation of macroautophagy and of the proteasome system in most cell types (17,18). Conversely, cells respond to inhibition of macroautophagy or the proteasome by constitutively activating CMA (19)(20)(21)(22).…”

Section: Chaperone-mediated Autophagy (Cma) 21 General Descriptionmentioning

confidence: 99%

Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone

Tekirdağ

Cuervo

2018

Journal of Biological Chemistry

291

236

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A variety of mechanisms deliver cytosolic materials to the lysosomal compartment for degradation through autophagy. Here, we focus on two autophagic pathways, chaperone-mediated autophagy and endosomal microautophagy that rely on the cytosolic chaperone hsc70 for substrate targeting. Although hsc70 participates in triage of proteins for degradation by different proteolytic systems, the common characteristic shared by these two forms of autophagy, is that hsc70 binds directly to a specific five amino acids motif in the cargo protein for its autophagic targeting. We summarize the current understanding of the molecular machineries behind each of these types of autophagy.

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Deficient Chaperone-Mediated Autophagy in Liver Leads to Metabolic Dysregulation

Cited by 274 publications

References 41 publications

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

Interplay of pathogenic forms of human tau with different autophagic pathways

Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone

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