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Article

Neddylation Regulates Class IIa and III Histone Deacetylases to Mediate Myoblast Differentiation

1
Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
2
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(17), 9509; https://doi.org/10.3390/ijms22179509
Submission received: 29 July 2021 / Revised: 26 August 2021 / Accepted: 28 August 2021 / Published: 1 September 2021
(This article belongs to the Special Issue Molecular Research on Muscle Protein and Myopathies)

Abstract

As the largest tissue in the body, skeletal muscle has multiple functions in movement and energy metabolism. Skeletal myogenesis is controlled by a transcriptional cascade including a set of muscle regulatory factors (MRFs) that includes Myogenic Differentiation 1 (MYOD1), Myocyte Enhancer Factor 2 (MEF2), and Myogenin (MYOG), which direct the fusion of myogenic myoblasts into multinucleated myotubes. Neddylation is a posttranslational modification that covalently conjugates ubiquitin-like NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to protein targets. Inhibition of neddylation impairs muscle differentiation; however, the underlying molecular mechanisms remain less explored. Here, we report that neddylation is temporally regulated during myoblast differentiation. Inhibition of neddylation through pharmacological blockade using MLN4924 (Pevonedistat) or genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1), a subunit of the E1 neddylation-activating enzyme, blocks terminal myoblast differentiation partially through repressing MYOG expression. Mechanistically, we found that neddylation deficiency enhances the mRNA and protein expressions of class IIa histone deacetylases 4 and 5 (HDAC4 and 5) and prevents the downregulation and nuclear export of class III HDAC (NAD-Dependent Protein Deacetylase Sirtuin-1, SIRT1), all of which have been shown to repress MYOD1-mediated MYOG transcriptional activation. Together, our findings for the first time identify the crucial role of neddylation in mediating class IIa and III HDAC co-repressors to control myogenic program and provide new insights into the mechanisms of muscle disease and regeneration.
Keywords: neddylation; histone deacetylases; myoblast differentiation neddylation; histone deacetylases; myoblast differentiation

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MDPI and ACS Style

Zhou, H.; Su, H.; Chen, W. Neddylation Regulates Class IIa and III Histone Deacetylases to Mediate Myoblast Differentiation. Int. J. Mol. Sci. 2021, 22, 9509. https://doi.org/10.3390/ijms22179509

AMA Style

Zhou H, Su H, Chen W. Neddylation Regulates Class IIa and III Histone Deacetylases to Mediate Myoblast Differentiation. International Journal of Molecular Sciences. 2021; 22(17):9509. https://doi.org/10.3390/ijms22179509

Chicago/Turabian Style

Zhou, Hongyi, Huabo Su, and Weiqin Chen. 2021. "Neddylation Regulates Class IIa and III Histone Deacetylases to Mediate Myoblast Differentiation" International Journal of Molecular Sciences 22, no. 17: 9509. https://doi.org/10.3390/ijms22179509

APA Style

Zhou, H., Su, H., & Chen, W. (2021). Neddylation Regulates Class IIa and III Histone Deacetylases to Mediate Myoblast Differentiation. International Journal of Molecular Sciences, 22(17), 9509. https://doi.org/10.3390/ijms22179509

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