Article

Taf1 Regulates Pax3 Protein by Monoubiquitination in Skeletal Muscle Progenitors

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Molecular cell (Impact Factor: 14.46). 12/2010; 40(5):749-61. DOI: 10.1016/j.molcel.2010.09.029
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ABSTRACT Pax3 plays critical roles during developmental and postnatal myogenesis. We have previously shown that levels of Pax3 protein are regulated by monoubiquitination and proteasomal degradation during postnatal myogenesis, but none of the key regulators of the monoubiquitination process were known. Here we show that Pax3 monoubiquitination is mediated by the ubiquitin-activating/conjugating activity of Taf1, a component of the core transcriptional machinery that was recently reported to be downregulated during myogenic differentiation. We show that Taf1 binds directly to Pax3 and overexpression of Taf1 increases the level of monoubiquitinated Pax3 and its degradation by the proteasome. A decrease of Taf1 results in a decrease in Pax3 monoubiquitination, an increase in the levels of Pax3 protein, and a concomitant increase in Pax3-mediated inhibition of myogenic differentiation and myoblast migration. These results suggest that Taf1 regulates Pax3 protein levels through its ability to mediate monoubiquitination, revealing a critical interaction between two proteins that are involved in distinct aspects of myogenic differentiation. Finally, these results suggest that the components of the core transcriptional are integrally involved in the process of myogenic differentiation, acting as nodal regulators of the differentiation program.

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Available from: Stéphane C Boutet, Aug 15, 2015
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    • "Pax3, a transcription factor with an important role in embryonic myogenesis, is regulated by the ubiquitin ligase Taf1. Taf1 associates directly with and ubiquitinates Pax3, resulting in its degradation by the proteasome (Boutet et al., 2010). MyoD (Tintignac et al., 2005) and myogenin (Jogo et al., 2009) can also be degraded by the UPS. "
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    • "Interestingly, SCs exhibit heterogeneity in terms of Pax3 expression in quiescence (Montarras et al., 2005; Relaix et al., 2006), a difference that cannot be explained by differences in protein stability (Boutet et al., 2010). Whereas virtually all quiescent SCs (QSCs) in most hindlimb muscles do not express Pax3, those in the diaphragm, ventral trunk muscles, and body wall muscle (e.g., serratus caudalis dorsalis), specific hindlimb muscles (e.g., gracilis), and about 50% of the forelimb muscles do express Pax3 (Montarras et al., 2005; Relaix et al., 2006). "
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    • "545 Non-canonical proteasomal signals Table 1. Ubiquitin ligases (E3) that synthesize 'non-canonical' ubiquitin chains that subsequently target substrates for proteasomal degradation E3 ligase (E2 enzyme) Type of ubiquitin chain Substrates References CHIP Chains based on lysine 6, 11, 48 and 63 HSP70 and HSP90 (Kundrat and Regan, 2010) MuRF1 (UBCH1 or heterodimer UBCH13–UEV1) Chains based on lysine 48 or 63 Troponin I (Kim et al., 2007) RSP5 Lysine-63-based chain Mga2 (Saeki et al., 2009) APC/C (UBCH10, UBE2S) Lysine-11-based chain BARD1, HMMR, HURP, NUSAP1 (Song and Rape, 2010) APC/C multiple monoubiquitylation, followed by formation of mixed chains Cyclin B1 (Kirkpatrick et al., 2006) SIAH1 (UBCH5a) Lysine-11-based chain -catenin (Dimitrova et al., 2010) RNF4 Heterologous SUMO-ubiquitin chains PolySUMOulated PML (Lallemand-Breitenbach et al., 2008; Tatham et al., 2008) LUBAC Linear Ubiquitin–GFP (Kirisako et al., 2006) CDC48–NPL4–UFD1 Linear tetraubiquitin PCNA (Zhao and Ulrich, 2010) TAF1 Monoubiquitin PAX3 (Boutet et al., 2010) mK3 "
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