Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm

Seung Hee Yoo, Jennifer A. Mohawk, Sandra M. Siepka, Yongli Shan, Seong Kwon Huh, Hee Kyung Hong, Izabela Kornblum, Vivek Kumar, Nobuya Koike, Ming Xu, Justin Nussbaum, Xinran Liu, Zheng Chen, Zhijian J. Chen, Carla B. Green, Joseph S. Takahashi

Research output: Contribution to journalArticle

155 Scopus citations

Abstract

Period determination in the mammalian circadian clock involves the turnover rate of the repressors CRY and PER. We show that CRY ubiquitination engages two competing E3 ligase complexes that either lengthen or shorten circadian period in mice. Cloning of a short-period circadian mutant, Past-time, revealed a glycine to glutamate missense mutation in Fbxl21, an F-box protein gene that is a paralog of Fbxl3 that targets the CRY proteins for degradation. While loss of function of FBXL3 leads to period lengthening, mutation of Fbxl21 causes period shortening. FBXL21 forms an SCF E3 ligase complex that slowly degrades CRY in the cytoplasm but antagonizes the stronger E3 ligase activity of FBXL3 in the nucleus. FBXL21 plays a dual role: protecting CRY from FBXL3 degradation in the nucleus and promoting CRY degradation within the cytoplasm. Thus, the balance and cellular compartmentalization of competing E3 ligases for CRY determine circadian period of the clock in mammals.

Original languageEnglish (US)
Pages (from-to)1091-1105
Number of pages15
JournalCell
Volume152
Issue number5
DOIs
StatePublished - Feb 28 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Yoo, S. H., Mohawk, J. A., Siepka, S. M., Shan, Y., Huh, S. K., Hong, H. K., Kornblum, I., Kumar, V., Koike, N., Xu, M., Nussbaum, J., Liu, X., Chen, Z., Chen, Z. J., Green, C. B., & Takahashi, J. S. (2013). Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell, 152(5), 1091-1105. https://doi.org/10.1016/j.cell.2013.01.055