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Published on: April 18, 2016
Smurf2 regulates the degradation of YY1
Hyung Min Jeong1, Sung Ho Lee1, Jinah Yum2
1College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, South Korea.
Abstract:
Transcription factor YY1 plays important roles in cell proliferation and differentiation. For example, YY1 represses the expression of muscle-specific genes and the degradation of YY1 is required for myocyte differentiation. The activity of YY1 can be regulated by various post-translational modifications; however, little is known about the regulatory mechanisms for YY1 degradation. In this report, we attempted to identify potential E3 ubiquitin ligases for YY1, and found that Smurf2 E3 ubiquitin ligase can negatively regulate YY1 protein level, but not mRNA level. Smurf2 interacted with YY1, induced the poly-ubiquitination of YY1 and shortened the half-life of YY1 protein. Conversely, an E3 ubiquitin ligase-defective mutant form of Smurf2 or knockdown of Smurf2 increased YY1 protein level. PPxY motif is a typical target recognition site for Smurf2, and the PPxY motif in YY1 was important for Smurf2 interaction and Smurf2-induced degradation of YY1 protein. In addition, Smurf2 reduced the YY1-mediated activation of a YY1-responsive reporter whereas Smurf2 knockdown increased it. Finally, Smurf2 relieved the suppression of p53 activity by YY1. Taken together, our results suggest a novel regulatory mechanism for YY1 function by Smurf2 in which the protein stability and transcriptional activity of YY1 are regulated by Smurf2 through the ubiquitin-proteasome-mediated degradation of YY1.
Insights
Smad ubiquitination regulatory factor 2 (Smurf2) targets transcription factor Yin Yang 1 (YY1) for degradation. This Smurf2-mediated YY1 degradation regulates cell differentiation and gene expression.
Area of Science:
- Molecular and Cellular Biology
- Biochemistry
- Genetics
Background:
- Transcription factor Yin Yang 1 (YY1) is crucial for cell proliferation and differentiation, notably repressing muscle-specific genes.
- YY1 degradation is essential for myocyte differentiation, but the regulatory mechanisms remain largely unknown.
- Post-translational modifications regulate YY1 activity, yet YY1 degradation pathways are poorly understood.
Purpose of the Study:
- To identify E3 ubiquitin ligases responsible for YY1 degradation.
- To elucidate the role of Smurf2 in regulating YY1 protein stability and function.
- To investigate the molecular mechanism by which Smurf2 controls YY1 levels and activity.
Main Methods:
- Investigated potential E3 ubiquitin ligases for YY1.
- Assessed the interaction between Smurf2 and YY1 using co-immunoprecipitation.
- Analyzed YY1 ubiquitination and protein half-life.
- Utilized Smurf2-defective mutants and Smurf2 knockdown experiments.
- Examined the impact of Smurf2 on YY1-responsive reporter activity and p53 activity.
Main Results:
- Smurf2 E3 ubiquitin ligase negatively regulates YY1 protein levels, but not mRNA levels.
- Smurf2 interacts with YY1, induces its poly-ubiquitination, and shortens its half-life.
- Smurf2 knockdown or use of a ligase-defective mutant increases YY1 protein levels.
- The PPxY motif in YY1 is critical for Smurf2 interaction and degradation.
- Smurf2 reduces YY1-mediated transcriptional activation and relieves YY1-mediated p53 suppression.
Conclusions:
- Smurf2 targets YY1 for ubiquitin-proteasome-mediated degradation, thereby regulating YY1 protein stability.
- Smurf2 controls YY1's transcriptional activity and its role in gene regulation.
- This study reveals a novel mechanism where Smurf2 modulates YY1 function through targeted protein degradation.
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