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

Abstract

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-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.

• Authors: Marvin Wirianto, Jiah Yang, Eunju Kim, Song Gao, Keshav Raj Paudel, Jong Min Choi, Jeehwan Choe, Gabrielle F Gloston, Precious Ademoji, Randika Parakramaweera, Jianping Jin, Karyn A Esser, Sung Yun Jung, Yong-Jian Geng, Hyun Kyoung Lee, Zheng Chen, Seung-Hee Yoo
• Journal: Cell reports (Cell Rep) Vol. 32 Issue 11 Pg. 108140 (09 15 2020) ISSN: 2211-1247 [Electronic] United States
• PMID: 32937135 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Connectin
• F-Box Proteins
• Fbxl21 protein, mouse
• Tcap protein, mouse
• SKP Cullin F-Box Protein Ligases
• Glycogen Synthase Kinase 3 beta
• Proteasome Endopeptidase Complex
• Lysine

Topics

• Amino Acid Sequence
• Animals
• Circadian Rhythm
• Connectin (chemistry, metabolism)
• F-Box Proteins (metabolism)
• Glycogen Synthase Kinase 3 beta (metabolism)
• HEK293 Cells
• Humans
• Lysine (metabolism)
• Mice, Inbred C57BL
• Muscle Fibers, Skeletal (metabolism)
• Muscle, Skeletal (physiology)
• Mutation (genetics)
• Phosphorylation
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis
• SKP Cullin F-Box Protein Ligases (metabolism)
• Substrate Specificity
• Ubiquitination