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

Cell reports 2020 Sep 15

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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. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

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. The GSK-3β-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function. Cell reports. 2020 Sep 15;32(11):108140