TY - JOUR
T1 - FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes
AU - Hirano, Arisa
AU - Yumimoto, Kanae
AU - Tsunematsu, Ryosuke
AU - Matsumoto, Masaki
AU - Oyama, Masaaki
AU - Kozuka-Hata, Hiroko
AU - Nakagawa, Tomoki
AU - Lanjakornsiripan, Darin
AU - Nakayama, Keiichi I.
AU - Fukada, Yoshitaka
N1 - Funding Information:
We thank Kentaro Hirose and Drs. Daisuke Kojima and Masaki Torii for their help with data analysis. We are grateful to Drs. Joseph S. Takahashi and Seung-Hee Yoo for communicating their unpublished results on Fbxl21 and to Drs. Steve A. Kay and Tsuyoshi Hirota for providing us with CRY1-Luc expression vectors. We also thank Jun Nakano and Drs. Hikari Yoshitane and Kimiko Shimizu for critical comments on the manuscript. This work was supported in part by Grants-in-Aid for Scientific research and by the Global COE program (Integrative Life Science Based on the Study of Biosignaling Mechanisms) from MEXT, Japan. A.H. is supported by JSPS Research Fellowships for Young Scientists.
PY - 2013/2/28
Y1 - 2013/2/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84874772651&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874772651&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2013.01.054
DO - 10.1016/j.cell.2013.01.054
M3 - Article
C2 - 23452856
AN - SCOPUS:84874772651
SN - 0092-8674
VL - 152
SP - 1106
EP - 1118
JO - Cell
JF - Cell
IS - 5
ER -