The circadian E3 ligase FBXL21 regulates myoblast differentiation and sarcomere architecture via MYOZ1 ubiquitination and NFAT signaling.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Ubiquitin-Protein Ligases*/genetics ; Ubiquitin-Protein Ligases*/metabolism ; F-Box Proteins*/genetics ; F-Box Proteins*/metabolism; Mice ; Animals ; Glycogen Synthase Kinase 3 beta/genetics ; Glycogen Synthase Kinase 3 beta/metabolism ; Sarcomeres/metabolism ; Cell Differentiation/genetics ; Ubiquitination ; Muscle, Skeletal/metabolism ; Myoblasts/metabolism ; NFATC Transcription Factors/genetics ; NFATC Transcription Factors/metabolism

Numerous molecular and physiological processes in the skeletal muscle undergo circadian time-dependent oscillations in accordance with daily activity/rest cycles. The circadian regulatory mechanisms underlying these cyclic processes, especially at the post-transcriptional level, are not well defined. Previously, we reported that the circadian E3 ligase FBXL21 mediates rhythmic degradation of the sarcomere protein TCAP in conjunction with GSK-3β, and Psttm mice harboring an Fbxl21 hypomorph allele show reduced muscle fiber diameter and impaired muscle function. To further elucidate the regulatory function of FBXL21 in skeletal muscle, we investigated another sarcomere protein, Myozenin1 (MYOZ1), that we identified as an FBXL21-binding protein from yeast 2-hybrid screening. We show that FBXL21 binding to MYOZ1 led to ubiquitination-mediated proteasomal degradation. GSK-3β co-expression and inhibition were found to accelerate and decelerate FBXL21-mediated MYOZ1 degradation, respectively. Previously, MYOZ1 has been shown to inhibit calcineurin/NFAT signaling important for muscle differentiation. In accordance, Fbxl21 KO and MyoZ1 KO in C2C12 cells impaired and enhanced myogenic differentiation respectively compared with control C2C12 cells, concomitant with distinct effects on NFAT nuclear localization and NFAT target gene expression. Importantly, in Psttm mice, both the levels and diurnal rhythm of NFAT2 nuclear localization were significantly diminished relative to wild-type mice, and circadian expression of NFAT target genes associated with muscle differentiation was also markedly dampened. Furthermore, Psttm mice exhibited significant disruption of sarcomere structure with a considerable excess of MYOZ1 accumulation in the Z-line. Taken together, our study illustrates a pivotal role of FBXL21 in sarcomere structure and muscle differentiation by regulating MYOZ1 degradation and NFAT2 signaling.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2022 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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R01 AR079220 United States AR NIAMS NIH HHS; R01 GM114424 United States GM NIGMS NIH HHS; R01 AG065984 United States AG NIA NIH HHS; R56 AG063746 United States AG NIA NIH HHS; R35 GM145232 United States GM NIGMS NIH HHS

EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
0 (NFATC Transcription Factors)
0 (Fbxl21 protein, mouse)
0 (F-Box Proteins)

Date Created: 20221227 Date Completed: 20230111 Latest Revision: 20240126

20240126

PMC9829178

10.1371/journal.pgen.1010574

36574402