SUMO Regulation of Cellular Processes by Van G. Wilson

Author:Van G. Wilson
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

12.5.2 Myocytes

Like basal keratinocytes , the muscle precursor cells known as myoblasts are proliferative cells that can stop replicating and enter terminal differentiation (Pownall et al. 2002). Upon differentiation the myoblasts start to fuse and form multinucleated myotubes, a process driven by the activity of the MyoD family of TFs in cooperation with the myocyte enhancer factor (MEF2) family (Tapscott 2005). Using the well-established C2C12 myoblast differentiation model, Riquelme et al. examined sumoylation during the differentiation process (Riquelme et al. 2006a). In contrast to keratinocytes , they showed that overall sumoylation of cellular targets declined for both SUMO1 and SUMO2/3 after induction of differentiation. Additionally, Ubc9 , which is expressed in both myocytes and myotubes, changes its distribution during differentiation and became more homogenously distributed throughout the nuclei of myotubes. Ubc9 knockdown with siRNA reduced global sumoylation, but had no effect on MyoD or myogenin expression, localization, or activity, suggesting that the effect of Ubc9 in not mediated directly through the MyoD family. Somewhat surprisingly since overall sumoylation decreases during myocyte differentiation, Ubc9 knockdown inhibited differentiation and resulted in decreased formation of myotubes. Neither apoptosis nor G2/M arrested cells increased under the knockdown conditions, so the mechanism of the Ubc9 effect is unclear, but must reflect subtle differences in target modification during knockdown compared to the sumoylation decrease seen during normal differentiation.

While the sumoylation of the MyoD family is uncertain, sumoylation of other myogenesis regulatory factors is now well documented. SnoN is an oncoprotein that also plays a role in muscle differentiation and was recently shown to be sumoylated at a single lysine residue in C2C12 cells (Wrighton et al. 2007). Mutation of the sumoylation site to arginine imbued SnoN with enhanced myogenic activity and enhanced transcriptional synergy with MyoD . During C2C12 cell differentiation, sumoylation of SnoN decreased slightly, consistent with decreased sumoylation promoting myocyte differentiation and myotube formation. Similarly, several members of the MEF2 family have been shown to be sumoylated, including MEF2A (Riquelme et al. 2006b), MEF2C (Gocke et al. 2005), and MEF2D (Gregoire et al. 2006), and at least for MEF2A (Riquelme et al. 2006b) and MEF2C (Kang et al. 2006) sumoylation is a negative regulator of transcriptional activity. While the role of MEF2 sumoylation in myocyte differentiation remains to be explored, the modification of these important regulatory factors by SUMO is clearly consistent with a functional role for sumoylation in growth and differentiation of this cell type. Furthermore, cross-talk between MEF2 sumoylation and other post-translational modifications such as phosphorylation (Gregoire et al. 2006) and acetylation (Gregoire et al. 2007) suggests exciting and complex regulatory feedback that may be critical for proper response to external stimuli and subsequent control of differentiation.

Several additional studies have begun to identify and characterize other sumoylation targets that are critical for muscle cell development. One of the members of the Pax family of transcriptional regulators, Pax7 is sumoylated on K85, and this modification is necessary to prevent myogenic differentiation of murine skeletal muscle cells (Luan et al. 2013). A lysine to

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