UBR5: A New Player in Protein Quality Control for Skeletal Muscle Growth and Remodeling

Abstract

A balance between protein synthesis and degradation regulates skeletal muscle size. Proteolytic mechanisms, like the ubiquitin-proteasome system, are critical processes in protein quality control. Counterintuitively, the E3 ubiquitin ligase, UBR5, appears to be involved in skeletal muscle hypertrophy and regrowth and interacts with protein synthesis. We present the novel hypothesis for protein quality control being critical for skeletal muscle growth and remodeling.

Keywords: N-degron pathway; exercise; proteasome system; protein turnover; skeletal muscle.

Figure 1.

Protein quality control of newly synthesized proteins: E3 surveillance perspective. Under growth conditions, demand for protein synthesis is placed within cells and tissues. Newly synthesized proteins from ribosomes will typically form into protein complexes where degron signals will be inaccessible for recognition [comprehensive review, refer to Pla-Prats and Thomä (2)]. However, not all proteins may be formed into complexes, leaving the likelihood of increased protein misfolding or excess orphan proteins to be present. In this scenario, the orphan protein presents a degron signal (depicted as red spots) that can be recognized by E3 ubiquitin ligases and the proteasome system for targeted ubiquitination and degradation. We hypothesize that E3s, like UBR5, function to provide protein surveillance for the degradation of excess or misfolded proteins during growth stimuli to maintain proteome integrity. (The figure was generated using BioRender.)

Figure 2.

N-degron and C-degron pathways in protein quality control. Protein substrates can develop destabilizing amino acid residues at the N-terminus and C-terminus that act as degradation signals [comprehensive review, refer to Sherpa et al. (25) and Varshavsky (25)]. The destabilization can occur at the primary or secondary structure level of the protein and be induced by an array of factors such as hypoxia, oxidative stress, and calpain activity. Modifications on the N-terminal residue, such as acetylation, can allow for subclasses of E3 ubiquitin ligases to recognize the protein substrates for ubiquitination and proteasomal degradation. The protein substrate upon ubiquitination is processed through the proteasome complex into short peptides for amino acid recycling. The N-degron pathway has received extensive investigation, whereas our understanding of C-degron pathways is in its infancy. In the C-degron pathway, complexes like the Kelch repeat complex (KLHDC) can form with E3 ubiquitin ligases (e.g., Cul2) to recognize the C-degron signal, leading to ubiquitination of the protein substrate. Our knowledge of these pathways has stemmed from cell model systems, with in vivo evidence illustrating how important components (e.g., E3 ubiquitin ligases) are in maintaining proteome integrity. However, very little is known about the role and function of E3s, like UBR7, Gid4, or Not4, in skeletal muscle health and proteostasis. (The figure was generated using BioRender.)

Figure 3.

Overview of experimental approaches used where UBR-box E3 ubiquitin ligases have been identified in skeletal muscle. UBR5 was first reported in resistance-trained human skeletal muscle. Subsequent studies utilizing human and rodent models have found UBR4, UBR5, and UBR7 mRNA expression and protein levels to be elevated under skeletal muscle growth conditions. Genetic manipulation of mouse and Drosophila models has uncovered roles for UBR4 and UBR5 in protein quality control and interactions with protein synthesis signaling, which are key in proteostasis and skeletal muscle function. Future studies are warranted to identify UBR-box E3 ligase substrates and explore how these E3s contribute to skeletal muscle growth. (The figure was generated using BioRender.)