Ubiquitination and Deubiquitination – update 2017
Résumé
A myriad of proteins have been found to be ubiquitinated in muscle. Many have a role in the signaling of muscle wasting, with effects not only on the ubiquitin pathway but also on autophagy. Interestingly at least one deubiquitinating enzyme is also implicated in muscle wasting.
This presentation focuses on new findings concerning MuRF1, which is so far the only muscle-specific ubiquitin ligase clearly shown to be involved in the breakdown of contractile proteins.
Recently Bowen et al. (2017) identified a compound targeting the central coiled coil domain of MuRF1 to inhibit muscle wasting. This compound prevented atrophy in myotubes induced by dexamethasone and attenuated muscle wasting in cardiac cachexia in mice. This reflected a positive effect on protein synthesis and a down-regulation of both apoptosis and ubiquitin-proteasome-dependent proteolysis.
We focused on the characterization of the muscle-specific MuRF1-E2 network (Polge et al. 2017). RING finger E3s like MuRF1 do not have ubiquitination properties, which are achieved by E2s. Using highly sensitive and complementary approaches (Surface Plasmon Resonance, Yeast three-Hybrid and split-GFP) we identify five E2 enzymes that physically interacted with MuRF1. We were also able to demonstrate that telethonin governed the affinity between MuRF1 and two E2s.
Whether these findings may be useful to specifically prevent the breakdown of contractile proteins in muscle wasting diseases remains to be demonstrated.
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