A Key Role for the Ubiquitin Ligase UBR4 in Myofiber Hypertrophy in Drosophila and Mice

• Published in: Cell reports (Cambridge) Vol. 28; no. 5; pp. 1268 - 1281.e6
• Main Authors: Hunt, Liam C., Stover, Jared, Haugen, Benard, Shaw, Timothy I., Li, Yuxin, Pagala, Vishwajeeth R., Finkelstein, David, Barton, Elisabeth R., Fan, Yiping, Labelle, Myriam, Peng, Junmin, Demontis, Fabio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.07.2019; Elsevier
• Subjects: Animals; Calmodulin-Binding Proteins - genetics; Calmodulin-Binding Proteins - metabolism; cancer cachexia; Drosophila; Drosophila melanogaster; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; HAT1; Hypertrophy; Mice; Muscle Proteins - genetics; Muscle Proteins - metabolism; muscle wasting; myofiber hypertrophy; myofiber size; Myofibrils - enzymology; proteolysis; skeletal muscle growth; ubiquitin ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; UBR4; ubiquitin ligase; myofiber size; skeletal muscle growth; Drosophila; cancer cachexia; HAT1; UBR4; muscle wasting; proteolysis; myofiber hypertrophy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.06.094

Skeletal muscle cell (myofiber) atrophy is a detrimental component of aging and cancer that primarily results from muscle protein degradation via the proteasome and ubiquitin ligases. Transcriptional upregulation of some ubiquitin ligases contributes to myofiber atrophy, but little is known about the role that most other ubiquitin ligases play in this process. To address this question, we have used RNAi screening in Drosophila to identify the function of > 320 evolutionarily conserved ubiquitin ligases in myofiber size regulation in vivo. We find that whereas RNAi for some ubiquitin ligases induces myofiber atrophy, loss of others (including the N-end rule ubiquitin ligase UBR4) promotes hypertrophy. In Drosophila and mouse myofibers, loss of UBR4 induces hypertrophy via decreased ubiquitination and degradation of a core set of target proteins, including the HAT1/RBBP4/RBBP7 histone-binding complex. Together, this study defines the repertoire of ubiquitin ligases that regulate myofiber size and the role of UBR4 in myofiber hypertrophy. [Display omitted] •RNAi screening identifies ubiquitin-related enzymes that regulate myofiber size•The ubiquitin ligase UBR4 regulates myofiber size in Drosophila and mice•Loss of UBR4 induces hypertrophy via decreased ubiquitination of target proteins•The HAT1/RBBP4/RBBP7 histone-binding complex is a UBR4 target key for hypertrophy Hunt et al. use the fruit fly Drosophila to identify ubiquitin-related enzymes that regulate skeletal muscle cell (myofiber) size, including the ubiquitin ligase UBR4. Loss of UBR4 promotes myofiber hypertrophy in Drosophila and mice via decreased ubiquitination and degradation of a core set of target proteins.