The GSK-3?-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function.

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-3? phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3? 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-3?-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function.
Mesh Terms:
Amino Acid Sequence, Animals, Circadian Rhythm, Connectin, F-Box Proteins, Glycogen Synthase Kinase 3 beta, HEK293 Cells, Humans, Lysine, Mice, Inbred C57BL, Muscle Fibers, Skeletal, Muscle, Skeletal, Mutation, Phosphorylation, Proteasome Endopeptidase Complex, Proteolysis, SKP Cullin F-Box Protein Ligases, Substrate Specificity, Ubiquitination
Cell Rep
Date: Dec. 15, 2019
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