Abstract
SUMMARYFBXL21 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-3β phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3β 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-3β-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function.
Highlights
The mammalian circadian clock regulates tissue-specific gene expression to control metabolism, physiology, and behavior (Cederroth et al, 2019; Takahashi, 2017)
FBXL21 Directly Regulates TCAP Degradation by F BoxDependent Ubiquitination we performed cycloheximide (CHX) chase assays to measure the effect of FBXLs on TCAP turnover
We show that the circadian E3 ligase FBXL21 governs rhythmic accumulation of TCAP
Summary
The mammalian circadian clock regulates tissue-specific gene expression to control metabolism, physiology, and behavior (Cederroth et al, 2019; Takahashi, 2017). The oscillator is governed by a complex mechanism encompassing transcriptional, posttranscriptional, and post-translational regulatory steps (Gallego and Virshup, 2007; Green, 2018). Ubiquitinationmediated proteasomal degradation is a critical post-translational mechanism in circadian oscillation, controlling clock protein degradation at the end of a circadian cycle prior to starting a new one (Stojkovic et al, 2014). Various E3 ligases and deubiquitinases regulate degradation of core clock proteins (Gallego and Virshup, 2007; Stojkovic et al, 2014), their functions and regulatory mechanisms in circadian physiology are not well understood
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