L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control

Lu, Jun; Periz, Goran; Lu, Yu Ning; Tang, Qing; Liu, Yang; Zhang, Tao; Shah, Yajas; Thombre, Ravi; Aljumaah, Reham; Li, Weixin; Mojsilovic-Petrovic, Jelena; Ji, Yon Ju; Johnson, Kenji; Kalb, Robert G.; Wang, Jiou

doi:10.1038/s41593-019-0384-5

Cited by 15 publications

(17 citation statements)

References 50 publications

(78 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…To date, our independent screens using mutant SOD1 C. elegans models have identified several suppressors of proteotoxicity, including UBE4B and LSD1 (18), L3MBTL1 (19), and USP7. Further studies have revealed a common theme shared by these regulators of proteotoxicity: They all modulate posttranslational modifications of transcription factors that control the expression of genes in protein quality control and thereby influence the degradation and clearance of misfolded proteins (18,19). A signaling hub in this regulatory network appears to be the transcription factor p53 (18,19); interestingly, USP7 has wellestablished roles in deubiquitinating p53 and its E3 ligase Hdm2 (42), suggesting that USP7 is part of the protein quality-control network.…”

Section: Discussionmentioning

confidence: 99%

“…Further studies have revealed a common theme shared by these regulators of proteotoxicity: They all modulate posttranslational modifications of transcription factors that control the expression of genes in protein quality control and thereby influence the degradation and clearance of misfolded proteins (18,19). A signaling hub in this regulatory network appears to be the transcription factor p53 (18,19); interestingly, USP7 has wellestablished roles in deubiquitinating p53 and its E3 ligase Hdm2 (42), suggesting that USP7 is part of the protein quality-control network. In the present study, we demonstrate that, in an analogous pathway, USP7 deubiquitinates the E3 ligase of SMAD2, which in turn regulates autophagy and protein quality control.…”

Section: Discussionmentioning

confidence: 99%

“…The Cys223Ser mutation was introduced into the pCI-Flag-USP7 plasmid by site-directed mutagenesis using primer-encoded nucleotide replacements and the HiFi Assembly kit (NEB). The control Flag-GUS plasmid expressing β-glucuronidase was previously described (19). The HA-ubiquitin-expressing plasmid was purchased from Addgene (18712).…”

Section: Methodsmentioning

confidence: 99%

“…Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1) and SET domain-containing protein 8 (SETD8) (19). These genes modify proteotoxicity through a p53-dependent transcriptional program that regulates the expression of the protein qualitycontrol machinery.…”

Section: Significancementioning

confidence: 99%

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USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

Zhang

Periz

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory switch in a protein quality-control system that defends against proteotoxicity. A genome-wide screen in a Caenorhabditis elegans model of SOD1-linked ALS identified the USP7 ortholog as a suppressor of proteotoxicity in the nervous system. The actions of USP7 orthologs on misfolded proteins were found to be conserved in Drosophila and mammalian cells. USP7 acts on protein quality control through the SMAD2 transcription modulator of the transforming growth factor β pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. Inhibition of USP7 protected against proteotoxicity in mammalian neurons, and SMAD2 was found to be dysregulated in the nervous systems of ALS patients. These findings reveal a regulatory pathway of protein quality control that is implicated in the proteotoxicity-associated neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 3 more Smart Citations

USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

Zhang

Periz

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Tubulin deacetylase NDST3 modulates lysosomal acidification: Implications in neurological diseases

Tang

Wang

2022

BioEssays

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Neurological diseases (NDs), featured by progressive dysfunctions of the nervous system, have become a growing burden for the aging populations. N‐Deacetylase and N‐sulfotransferase 3 (NDST3) is known to catalyze deacetylation and N‐sulfation on disaccharide substrates. Recently, NDST3 is identified as a novel deacetylase for tubulin, and its newly recognized role in modulating microtubule acetylation and lysosomal acidification provides fresh insights into ND therapeutic approaches using NDST3 as a target. Microtubule acetylation and lysosomal acidification have been reported to be critical for activities in neurons, implying that the regulators of these two biological processes, such as the previously known microtubule deacetylases, histone deacetylase 6 (HDAC6) and sirtuin 2 (SIRT2), could play important roles in various NDs. Aberrant NDST3 expression or tubulin acetylation has been observed in an increasing number of NDs, including amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), schizophrenia and bipolar disorder, Alzheimer's disease (AD), and Parkinson's disease (PD), suggesting that NDST3 is a key player in the pathogenesis of NDs and may serve as a target for development of new treatment of NDs.

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The Long Non-Coding RNA NR3C2-8:1 Promotes p53-Mediated Apoptosis through the miR-129-5p/USP10 Axis in Amyotrophic Lateral Sclerosis

Pang,

Yu,

Zhao

et al. 2024

Mol Neurobiol

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Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a form of apoptosis, but the mechanisms underlying this neuronal cell death remain unclear. Numerous studies demonstrate abnormally elevated and active p53 in the central nervous system of ALS patients. Activation of p53-regulated pro-apoptotic signaling pathways may trigger motor neuron death. We previously reported decreased expression of the long non-coding RNA NR3C2-8:1 (Lnc-NR3C) in leukocytes of ALS patients. Here, we show lnc-NR3C promotes p53-mediated cell death in ALS by upregulating USP10 and promoting lnc-NR3C-triggered p53 activation, resulting in cell death. Conversely, lnc-NR3C knockdown inhibited USP10-triggered p53 activation, thereby protecting cells against oxidative stress. As a competitive endogenous RNA, lnc-NR3C competitively binds miR-129-5p, regulating the usp10/p53 axis. Elucidating the link between Lnc-NR3C and the USP10/p53 axis in an ALS cell model reveals a role for long non-coding RNAs in activating apoptosis. This provides new therapeutic opportunities in ALS.

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L3MBTL1 regulates ALS/FTD-associated proteotoxicity and quality control

Cited by 15 publications

References 50 publications

USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

Tubulin deacetylase NDST3 modulates lysosomal acidification: Implications in neurological diseases

The Long Non-Coding RNA NR3C2-8:1 Promotes p53-Mediated Apoptosis through the miR-129-5p/USP10 Axis in Amyotrophic Lateral Sclerosis

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