Blocking the association of HDAC4 with MAP1S accelerates autophagy clearance of mutant Huntingtin

Yue, Fei; Li, Wenjiao; Zou, Jing; Chen, Qi; Xu, Guibin; Huang, Hai; Xu, Zhen; Zhang, Sheng; Gallinari, Paola; Wang, Fen; McKeehan, Wallace L.; Liu, Leyuan

doi:10.18632/aging.100818

Cited by 21 publications

(35 citation statements)

References 45 publications

(59 reference statements)

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“…Other antibodies, siRNAs and reagents were described by Zou et al (26) and Yue el al. (19). Type IV collagenase (11088874103) was from Roche.…”

Section: Methodsmentioning

confidence: 99%

“…Cell transfection, immunoprecipitation, immunoblot analysis and confocal fluorescent microscopy were performed as previously described (19,26). Heavy membrane pellet, light membrane pellet, and soluble fraction were prepared from HeLa cells as described (10).…”

Section: Methodsmentioning

confidence: 99%

“…Higher levels of MAP1S in tumor tissues predict longer survivals for human patients suffering from either prostate adenocarcinomas (17) or clear cell renal cell carcinomas (18). MAP1S interacts with HDAC4 through a specific domain, and the inhibition of HDAC4 increases the acetylation and stability of MAP1S and activates autophagy flux to degrade aggregates of mutant huntingtin proteins related to Huntington’s disease (19). Thus, increasing the levels of MAP1S in mice may cause the activation of autophagy flux to expand lifespans, reduce liver fibrosis and suppress HCC.…”

Section: Introductionmentioning

confidence: 99%

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Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy

et al. 2017

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Liver fibrosis and hepatocellular carcinoma (HCC) have worldwide impact but continue to lack safe, low cost and effective treatments. In this study, we show how the simple polyamine spermidine can relieve cancer cell defects in autophagy which trigger oxidative stress-induced cell death and promote liver fibrosis and HCC. We found that the autophagic marker protein LC3 interacted with the microtubule-associated protein MAP1S which positively regulated autophagy flux in cells. MAP1S stability was regulated in turn by its interaction with the histone deacetylase HDAC4. Notably, MAP1S-deficient mice exhibited a 20% reduction in median survival and developed severe liver fibrosis and HCC under stress. Wild-type mice or cells treated with spermidine exhibited a relative increase in MAP1S stability and autophagy signaling via depletion of cytosolic HDAC4. Extending recent evidence that orally administered spermidine can extend lifespan in mice, we determined that life extension of up to 25% can be produced by lifelong administration which also reduced liver fibrosis and HCC foci as induced by chemical insults. Genetic investigations established that these observed impacts of oral spermidine administration relied upon MAP1S-mediated autophagy. Our findings offer a preclinical proof of concept for the administration of oral spermidine to prevent liver fibrosis and HCC and potentially extend lifespan.

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“…Lysates from liver tissues collected from mice at different ages or from cultured cells were prepared and analyzed by immunoblotting as described (Zou et al ., 2013, 2014). Immortalized MEFs were developed from wild‐type and MAP1S −/− mice (Xie et al ., 2011a), and cultured in the same way as we described before (Xie et al ., 2011a; Yue et al ., 2015). To examine the impact of MAP1S on autophagy flux, MEFs were cultured in the absence or presence of 10 n m bafilomycin A1 for 6 h. The LC3‐II levels were adjusted by their respective levels of β‐actin, and the increased levels of LC3‐II after bafilomycin A1 treatment were designated as the values of autophagy flux according to the established guidelines (Klionsky et al ., 2012).…”

Section: Methodsmentioning

confidence: 99%

Defects inMAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Zou

Yue

et al. 2016

Aging Cell

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SummaryAutophagy is a cellular process that executes the turnover of dysfunctional organelles and misfolded or abnormally aggregated proteins. Microtubule‐associated protein MAP1S interacts with autophagy marker LC3 and positively regulates autophagy flux. LC3 binds with fibronectin mRNA and facilitates its translation. The synthesized fibronectin protein is exported to cell surface to initiate the assembly of fibronectin extracellular matrix. Fibronectin is degraded in lysosomes after it is engulfed into cytosol via endocytosis. Here, we show that defects in MAP1S‐mediated autophagy trigger oxidative stress, sinusoidal dilation, and lifespan reduction. Overexpression of LC3 in wild‐type mice increases the levels of fibronectin and γ‐H2 AX, a marker of DNA double‐strand breakage. LC3‐induced fibronectin is efficiently degraded in lysosomes to maintain a balance of fibronectin levels in wild‐type mice so that the mice live a normal term of lifespan. In the LC3 transgenic mice with MAP1S deleted, LC3 enhances the synthesis of fibronectin but the MAP1S depletion causes an impairment of the lysosomal degradation of fibronectin. The accumulation of fibronectin protein promotes liver fibrosis, induces an accumulation of cell population at the G0/G1 stage, and further intensifies oxidative stress and sinusoidal dilatation. The LC3‐induced overexpression of fibronectin imposes stresses on MAP1S‐deficient mice and dramatically reduces their lifespans. Therefore, MAP1S‐mediated autophagy plays an important role in maintaining mouse lifespan especially in the presence of extra amount of fibronectin.

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“…First, overexpression of miR-22 has a protective effect on mHTT model cells, which may be mediated by HDAC4 reduction as HDAC4 is a target gene of miR-22 (Jovicic et al, 2013). Second, HDAC4 interacts with microtubule associated protein 1S (MAP1S) resulting in MAP1S destabilization and reduction, subsequently suppressing the clearance of mHTT aggregates and potentiating the toxicity of mHTT to cultured cells (Yue et al, 2015). Moreover, HDAC4 is associated with HTT in a polyglutamine-length-dependent manner and co-localized with cytoplasmic aggregates.…”

Section: Aberrant Hdac4 Expression/localization In Neurodegenerative mentioning

confidence: 99%

Aberrant Expression of Histone Deacetylases 4 in Cognitive Disorders: Molecular Mechanisms and a Potential Target

Wu¹,

Hou

Wang

et al. 2016

Front. Mol. Neurosci.

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Histone acetylation is a major mechanism of chromatin remodeling, contributing to epigenetic regulation of gene transcription. Histone deacetylases (HDACs) are involved in both physiological and pathological conditions by regulating the status of histone acetylation. Although histone deacetylase 4 (HDAC4), a member of the HDAC family, may lack HDAC activity, it is actively involved in regulating the transcription of genes involved in synaptic plasticity, neuronal survival, and neurodevelopment by interacting with transcription factors, signal transduction molecules and HDAC3, another member of the HDAC family. HDAC4 is highly expressed in brain and its homeostasis is crucial for the maintenance of cognitive function. Accumulated evidence shows that HDAC4 expression is dysregulated in several brain disorders, including neurodegenerative diseases and mental disorders. Moreover, cognitive impairment is a characteristic feature of these diseases. It indicates that aberrant HDAC4 expression plays a pivotal role in cognitive impairment of these disorders. This review aims to describe the current understanding of HDAC4’s role in the maintenance of cognitive function and its dysregulation in neurodegenerative diseases and mental disorders, discuss underlying molecular mechanisms, and provide an outlook into targeting HDAC4 as a potential therapeutic approach to rescue cognitive impairment in these diseases.

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Blocking the association of HDAC4 with MAP1S accelerates autophagy clearance of mutant Huntingtin

Cited by 21 publications

References 45 publications

Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy

Defects inMAP1S‐mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed

Aberrant Expression of Histone Deacetylases 4 in Cognitive Disorders: Molecular Mechanisms and a Potential Target

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