FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes

Arisa Hirano, Kanae Yumimoto, Ryosuke Tsunematsu, Masaki Matsumoto, Masaaki Oyama, Hiroko Kozuka-Hata, Tomoki Nakagawa, Darin Lanjakornsiripan, Keiichi I. Nakayama, Yoshitaka Fukada

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128 Citations (Scopus)

Abstract

In the mammalian circadian clockwork, CRY1 and CRY2 repressor proteins are regulated by posttranslational modifications for temporally coordinated transcription of clock genes. Previous studies revealed that FBXL3, an F-box-type E3 ligase, ubiquitinates CRYs and mediates their degradation. Here, we found that FBXL21 also ubiquitinates CRYs but counteracts FBXL3. Fbxl21 -/- mice exhibited normal periodicity of wheel-running rhythms with compromised organization of daily activities, while an extremely long-period phenotype of Fbxl3-/- mice was attenuated in Fbxl3/Fbxl21 double-knockout mice. The double knockout destabilized the behavioral rhythms progressively and sometimes elicited arrhythmicity. Surprisingly, FBXL21 stabilized CRYs and antagonized the destabilizing action by FBXL3. Predominantly cytosolic distribution of FBXL21 contrasts with nuclear localization of FBXL3. These results emphasize the physiological importance of antagonizing actions between FBXL21 and FBXL3 on CRYs, and their combined actions at different subcellular locations stabilize oscillation of the circadian clock.

Original languageEnglish
Pages (from-to)1106-1118
Number of pages13
JournalCell
Volume152
Issue number5
DOIs
Publication statusPublished - Feb 28 2013

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hirano, A., Yumimoto, K., Tsunematsu, R., Matsumoto, M., Oyama, M., Kozuka-Hata, H., ... Fukada, Y. (2013). FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell, 152(5), 1106-1118. https://doi.org/10.1016/j.cell.2013.01.054