{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nFBXL21 is a key circadian E3 ligase that modulates the stability of core clock repressors. In the nucleus, FBXL21 antagonizes a more potent E3 ligase, FBXL3, thereby protecting the CRY proteins from accelerated degradation, while in the cytoplasm it mediates a slower, yet essential, ubiquitination and degradation of CRY. This dual, compartment-specific role of FBXL21 facilitates the fine-tuning of circadian period, as evidenced by genetic mutations that produce contrasting phenotypic effects on period length."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its central role in controlling the molecular clock, FBXL21 functions in a tissue-specific manner to influence skeletal muscle physiology. A clock-controlled regulatory pathway involves the sarcomere component TCAP, which is targeted by FBXL21 for degradation in a manner that is tightly regulated by phosphorylation through GSK-3β. Disruption of this regulatory axis in mutant models leads to alterations in TCAP oscillation and substantial defects in muscle structure and function, highlighting the importance of circadian regulation in peripheral tissue integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther extending its impact on muscle homeostasis, FBXL21 also targets MYOZ1, a known inhibitor of calcineurin/NFAT signaling critical for myogenic differentiation. FBXL21-mediated ubiquitination of MYOZ1, which is enhanced by GSK-3β activity, ensures proper proteasomal degradation of MYOZ1, thereby facilitating NFAT nuclear localization and the expression of genes required for muscle differentiation. Disruption of FBXL21 function leads to excess MYOZ1 accumulation, aberrant NFAT signaling and significant impairments in sarcomere organization and muscle differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Seung-Hee Yoo, Jennifer A Mohawk, Sandra M Siepka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2013.01.055"}], "href": "https://doi.org/10.1016/j.cell.2013.01.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23452855"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23452855"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Arisa Hirano, Kanae Yumimoto, Ryosuke Tsunematsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2013.01.054"}], "href": "https://doi.org/10.1016/j.cell.2013.01.054"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23452856"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23452856"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marvin Wirianto, Jiah Yang, Eunju Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The GSK-3β-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.108140"}], "href": "https://doi.org/10.1016/j.celrep.2020.108140"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32937135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32937135"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ji Ye Lim, Eunju Kim, Collin M Douglas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The circadian E3 ligase FBXL21 regulates myoblast differentiation and sarcomere architecture via MYOZ1 ubiquitination and NFAT signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1010574"}], "href": "https://doi.org/10.1371/journal.pgen.1010574"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36574402"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36574402"}]}]}]}