title: FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes.
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.
authors: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Arisa
authors: A
authors: Hirano
authors: Kanae
authors: K
authors: Yumimoto
authors: Ryosuke
authors: R
authors: Tsunematsu
authors: Masaki
authors: M
authors: Matsumoto
authors: Masaaki
authors: M
authors: Oyama
authors: Hiroko
authors: H
authors: Kozuka-Hata
authors: Tomoki
authors: T
authors: Nakagawa
authors: Darin
authors: D
authors: Lanjakornsiripan
authors: Keiichi I
authors: KI
authors: Nakayama
authors: Yoshitaka
authors: Y
authors: Fukada
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057906:Circadian Clocks; D056931:Cryptochromes / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D016415:Sequence Alignment; D054875:Ubiquitination
chemical_list: C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D044783:F-Box Proteins; C580664:Fbxl21 protein, mouse; C519794:Fbxl3 protein, mouse; D046912:Multiprotein Complexes