Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity

Pi, Huifeng; Li, Min; Tian, Li; Yang, Zhiqi; Yu, Zhengping; Zhou, Zhou

doi:10.1038/srep43466

Cited by 60 publications

(41 citation statements)

References 60 publications

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“…The AAV2/PHP.eB virions carrying the Serpina3n ORF (AAV-serpina3n) or mScarlet (red fluorescent protein) as a control (AAV-null) were used and generated by OBIO Technology, China, as we previously reported. 37…”

Section: Generation Of Recombinant Adeno-associated Virions (Aavs) mentioning

confidence: 99%

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Liu

Hong

et al. 2019

Journal of Pineal Research

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Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well‐known anti‐inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT‐induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy‐like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT‐induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT‐induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT‐induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT‐induced neurotoxicity by inhibiting SERPINA3N‐mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT‐induced neurotoxicity in clinical practice.

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Section: Generation Of Recombinant Adeno-associated Virions (Aavs) mentioning

confidence: 99%

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Liu

Hong

et al. 2019

Journal of Pineal Research

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“…Then, the cells were washed with PBS and run in an Infinite™ M200 Microplate Reader to analyse fluorescence intensity (excitation: 485 and emission: 530). 24…”

Section: Lysosomal Ph Measurementmentioning

confidence: 99%

SCD1 activation impedes foam cell formation by inducing lipophagy in oxLDL‐treated human vascular smooth muscle cells

Wang

Liu

et al. 2019

J Cellular Molecular Medi

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The formation of fat‐laden foam cells, which contributes to the fatty streaks in the plaques of atheromas, is an important process in atherosclerosis. Vascular smooth muscle cells (VSMCs) are a critical origin of foam cells. However, the mechanisms that underlie VSMC foam cell formation are not yet completely understood. Here, we demonstrated that oxidized low‐density lipoprotein (oxLDL) inhibited lipophagy by suppressing lipid droplet (LD)‐lysosome fusion and increased VSMC foam cell formation. Moreover, although oxLDL treatment inhibited lysosomal biogenesis, it had no significant effect on lysosomal proteolysis and lysosomal pH. Notably, through TMT‐based quantitative proteomic analysis and database searching, 94 differentially expressed proteins were identified, of which 54 were increased and 40 were decreased in the oxLDL group compared with those in the control group. Subsequently, SCD1, a protein of interest, was further investigated. SCD1 levels in the VSMCs were down‐regulated by exposure to oxLDL in a time‐dependent manner and the interaction between SCD1 and LDs was also disrupted by oxLDL. Importantly, SCD1 overexpression enhanced LD‐lysosome fusion, increased lysosomal biogenesis and inhibited VSMC foam cell formation by activating TFEB nuclear translocation and its reporter activity. Modulation of the SCD1/TFEB‐mediated lipophagy machinery may offer novel therapeutic approaches for the treatment of atherosclerosis.

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“…Failure of fusion of autophagosomes with lysosomes can impair autophagic flux (Eskelinen et al, 2002). To test if this could be a cause of reduced autophagy flux in matrix-detached cells, we performed immunostaining for LAMP2, a lysosomal marker (Eskelinen et al, 2002), and gauged its co-localization with GFP-LC3 puncta that is indicative of autophagosomelysosome fusion (Pi et al, 2017) using confocal microscopy. Quantitative co-localization analysis (as described in methods) revealed less LAMP2/LC3 co-localized punctae in a large proportion (~70%) of matrix-deprived cells ( Figures 2D &S2B), suggestive of blocked autophagy maturation in these cells.…”

Section: Erk Signaling Heterogeneity Regulates Autophagy Maturation Imentioning

confidence: 99%

Feedback loops involving ERK, AMPK and TFEB generate non-genetic heterogeneity that allows cells to evade anoikis

Kumar

Hari

Jolly

et al. 2019

Preprint

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Running titleNon-genetic heterogeneity in matrix-detached cells Keywords: AMP-activated protein kinase (AMPK), Extracellular signal-regulated kinase (ERK), Phosphoprotein enriched in astrocytes 15 kDa (PEA15), TFEB, Autophagy maturation, Anoikis.Financial support: This work was majorly supported by grants from the Wellcome Trust-DBT India Alliance (IA) Senior Research Fellowship (500112/Z/09/Z) to AR. AbstractSome solid tumor cells escape death triggered by matrix-deprivation and cause cancer spread through metastatic growth. The role of phenotypic plasticity in this adaptation remains unknown. We recently identified a double-negative feedback loop between pAMPK (phospho-AMPK) and pAkt (phospho-Akt) that regulates the switch between attached and detached states of cancer cells. In this study, we show that matrix-detachment itself can give rise to two subpopulations with varying ERK signaling levels and autophagy flux. Cells with elevated ERK activity show autophagy maturation arrest leading to anoikis, whereas those with low ERK activity overcome this block and generate anchorage-independent colonies.Investigating upstream, we show a novel role of AMPK-mediated phosphorylation of PEA15 in inhibiting ERK activity by reducing the formation of MEK-ERK complex. Consequently, cells with higher AMPK activity have lower phospho-ERK, and this heterogeneity is reflected in vivo. Exploring downstream, we demonstrate that ERK inhibition leads to upregulation of TFEB, a major regulator of lysosome biogenesis and autophagy.Overexpression of TFEB not only rescues the defect in autophagy flux, but also re-inforces AMPK signaling, thus revealing a positive feedback loop between AMPK and TFEB.Mathematical modelling of this loop shows that it can give rise to two distinct cellular phenotypes -pAMPK high /TFEB high /pERK low and pAMPK low / TFEB low /pERK high -and phenotype switching, thus offering a mechanistic basis for our observations for non-genetic heterogeneity in anoikis adaptation. Significantly, we observed these heterogeneous cell states in patient-derived circulating tumor cells also. Thus, our work unravels a novel feedback loop that can generate non-genetic heterogeneity within matrix-detached cancer cells; targeting such loops may offer novel therapeutic approaches for restricting metastasis and improving therapeutic efficacy. was analysed on H&E stained slides of the tissue section. Images were taken using I X 71Olympus inverted microscope. Microarray data analysisMDA-MB-231 cells were cultured for 24 hours in attached or matrix-deprived condition and MDA-MB-231 cells stably expressing shAMPKα2 cultured in suspension condition.Microarray assay was done after harvesting cells at indicated time points. RNA isolation was performed using RNeasy minikit (Cat No. 74104; Qiagen). Cy3 labelling was done by Agilent's Quick-Amp labeling Kit (Cat. No. 5190-0442) followed by hybridization on Agilent's In situ Hybridization Kit (Cat No.5188-5242). The comparison was done between expression of same genes across test sample and c...

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Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity

Cited by 60 publications

References 60 publications

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

SCD1 activation impedes foam cell formation by inducing lipophagy in oxLDL‐treated human vascular smooth muscle cells

Feedback loops involving ERK, AMPK and TFEB generate non-genetic heterogeneity that allows cells to evade anoikis

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