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Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke.

ABSTRACT: EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. Previously, we showed that EZH2 downregulation enhances neuron differentiation of human mesenchymal stem cells (hMSCs); however, the underlying mechanisms of EZH2-regulated neuron differentiation are still unclear. Here, we identify Smurf2 as the E3 ubiquitin ligase responsible for the polyubiquitination and proteasome-mediated degradation of EZH2, which is required for neuron differentiation. A ChIP-on-chip screen combined with gene microarray analysis revealed that PPAR? was the only gene involved in neuron differentiation with significant changes in both its modification and expression status during differentiation. Moreover, knocking down PPAR? prevented cells from undergoing efficient neuron differentiation. In animal model, rats implanted with intracerebral EZH2-knocked-down hMSCs or hMSCs plus treatment with PPAR? agonist (rosiglitazone) showed better improvement than those without EZH2 knockdown or rosiglitazone treatment after a stroke. Together, our results support Smurf2 as a regulator of EZH2 turnover to facilitate PPAR? expression, which is specifically required for neuron differentiation, providing a molecular mechanism for clinical applications in the neurodegenerative diseases.

SUBMITTER: Yu YL

PROVIDER: S-EPMC3628108 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke.

Yu Yung-Luen YL Chou Ruey-Hwang RH Shyu Woei-Cherng WC Hsieh Shu-Ching SC Wu Chen-Shiou CS Chiang Shu-Ya SY Chang Wei-Jung WJ Chen Jia-Ni JN Tseng Yen-Ju YJ Lin Yu-Hsuan YH Lee Wei W Yeh Su-Peng SP Hsu Jennifer L JL Yang Cheng-Chieh CC Hung Shih-Chieh SC Hung Mien-Chie MC

EMBO molecular medicine 20130325 4

EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. Previously, we showed that EZH2 downregulation enhances neuron differentiation of human mesenchymal stem cells (hMSCs); however, the underlying mechanisms of EZH2-regulated neuron differentiation are still unclear. Here, we identify Smurf2 as the E3 ubiquitin ligase responsible for the polyubiquitination and proteasome-mediated degradation of EZH2, which is req ...[more]

PMID: 23526793

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Project description:Although pontine strokes account for a small percentage of all ischaemic events, they can be associated with significant initial disability. These lesions may be missed on computed tomography and therefore magnetic resonance imaging is generally preferred for the assessment of brainstem strokes. The aetiopathogenesis of isolated pontine infarcts, not due to a significant compromise (occlusion or dissection) in the vertebrobasilar territory, still remains to be fully characterised. These strokes present with different symptoms, depending on the lesion location and size, partly reflecting the anatomical variability of the vertebrobasilar vessels. Progressive neurological deterioration is relatively common and has been associated with the extension of such lesions. However, many patients with significant infarcts in the pons will do well in the future and initial diffusion-weighted imaging may not add useful prognostication to the clinical assessment. We discuss here a case where an initially progressive presentation was associated with a marked improvement in both clinical and radiological assessments at 42 days.A 49-year-old white British man presented with left-sided weakness, incoordination, unsteadiness, cerebellar ataxic dysarthria and dysphonia. A baseline magnetic resonance imaging scan with diffusion-weighted imaging, T1-weighted and T2-weighted sequences showed an acute bilateral pontine infarct. On a repeat scan at 42 days, there was a 57.5% decrease in the size of the lesion on the high-resolution three-dimensional T1-weighted image and a corresponding improvement in the symptoms and the clinical assessments of this patient. The reduction in infarct size was also comparable to the decrease calculated between the baseline diffusion-weighted and the follow-up fluid attenuated inversion recovery sequences.This case report discusses the significant clinical improvement and corresponding lesion reduction in a patient that presented with worsening neurological symptoms and was diagnosed with acute bilateral ischaemic pontine infarction. Further studies, utilising structural and functional magnetic resonance imaging with follow-up scans, are needed to provide better insights into the underlying aetiopathology and recovery mechanisms of pontine stroke. These will help define the relationship between imaging parameters and outcome allowing for better prognosis along with the development of relevant rehabilitation programs for this group of patients.

Project description:Transforming growth factor-? (TGF-?) acts as a key cytokine in epithelial-mesenchymal transition (EMT) and myofibroblast differentiation, which are important for normal tissue repair and fibrotic diseases. Ubiquitylation and proteasomal degradation of TGF-? signaling proteins acts as a regulatory mechanism for the precise control of TGF-? signaling. SMAD-specific ubiquitin E3 ligase (SMAD ubiquitination regulatory factor 2, SMURF2) controls TGF-? signaling proteins including the TGF-? receptor (TGFR) and SMAD2/3. Here, we report that tetratricopeptide repeat domain 3 (TTC3), a ubiquitin E3 ligase, positively regulates TGF-?1-induced EMT and myofibroblast differentiation, through inducing ubiquitylation and proteasomal degradation of SMURF2. In human bronchial epithelial cells (BEAS-2B) and normal human lung fibroblasts, TTC3 knockdown suppressed TGF-?1-induced EMT and myofibroblast differentiation, respectively. Similarly, when TTC3 expression was suppressed, the TGF-?1-stimulated elevation of p-SMAD2, SMAD2, p-SMAD3, and SMAD3 were inhibited. In contrast, overexpression of TTC3 caused both EMT and myofibroblast differentiation in the absence of TGF-?1 treatment. TGF-?1 reduced SMURF2 levels and TTC3 overexpression led to a further decrease in SMURF2 levels, while TTC3 knockdown inhibited TGF-?1-induced SMURF2 reduction. In cell and in vitro ubiquitylation assays demonstrated TTC3-mediated SMURF2 ubiquitylation, and coimmunoprecipitation assays established the binding between SMURF2 and TTC3. TGF-?1-induced TTC3 expression was inhibited by the knockdown of SMAD2 and SMAD3. Finally, Ttc3 mRNA levels were significantly increased and Smurf2 protein levels were significantly decreased in the lungs of mice treated with bleomycin as compared with the lungs of control mice. Collectively, these data suggest that TTC3 may contribute to TGF-?1-induced EMT and myofibroblast differentiation, potentially through SMURF2 ubiquitylation/proteasomal degradation and subsequent inhibition of SMURF2-mediated suppression of SMAD2 and SMAD3, which in turn induces TTC3 expression.

Dataset Information

Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke.

Publications

Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke.

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