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Ubiquitin-proteasome system in skeletal muscle protein degradation

Muscle wasting due to skeletal muscle protein degradation complicates many diseases (e.g. cancer, infection, stroke) as well as normal aging. Our goal is to identify key enzymes in the ubiquitin proteasome system that are responsible for the activation of protein degradation and could be pharmacologically inhibited to prevent or treat muscle wasting. We identified USP19 as a deubiquitinating enzyme that is induced in atrophying skeletal muscle. Our cellular and transgenic knock out studies indicate that this enzyme plays an important role not just in muscle wasting, but has a broader effect on metabolism including physical activity and glucose homeostasis. We are currently exploring mechanisms arid the potential drug targeting of this enzyme.

Ubiquitin-proteasome system during spermatogenesis

Highly regulated degradation of proteins plays important roles in the proliferative, meiotic and cellular remodeling phases of spermatogenesis. We previously demonstrated the activation of ubiquitination during spermatogenesis and have subsequently identified key ubiquitin system enzymes involved in this process such as the Huwe1 ubiquitin ligase and the USP2 deubiquitinating enzyme. We are presently identifying the substrates that mediate their effects.