| First Author | Wirianto M | Year | 2020 |
| Journal | Cell Rep | Volume | 32 |
| Issue | 11 | Pages | 108140 |
| PubMed ID | 32937135 | Mgi Jnum | J:298890 |
| Mgi Id | MGI:6489012 | Doi | 10.1016/j.celrep.2020.108140 |
| Citation | Wirianto M, et al. (2020) The GSK-3beta-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function. Cell Rep 32(11):108140 |
| abstractText | FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. FBXL21 interacts with TCAP in a circadian manner antiphasic to TCAP accumulation in skeletal muscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3beta inhibition or knockdown diminishes FBXL21-Cul1 complex formation and delays FBXL21-mediated TCAP degradation. Finally, Psttm mice show significant skeletal muscle defects, including impaired fiber size, exercise tolerance, grip strength, and response to glucocorticoid-induced atrophy, in conjunction with cardiac dysfunction. These data highlight a circadian regulatory pathway where a GSK-3beta-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function. |
