Degradation of the Neurospora circadian clock protein FREQUENCY through the ubiquitin-proteasome pathway
Degradation of the Neurospora circadian clock protein FREQUENCY through the ubiquitin-proteasome pathway
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DOI：
10.1042/bst0330953
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发表时间：
2005-11-01
影响因子：
3.9
通讯作者：
Liu, Y
中科院分区：
文献类型：
--
作者：
He, Q;Liu, Y
脉孢菌生物钟蛋白FREQUENCY（FRQ）的磷酸化通过泛素-蛋白酶体途径促进其降解。FRQ的泛素化需要FWD-1（F-box/WD-40 repeat-containing protein-1），它是SCF（SKP/Cullin/F-box）型泛素连接酶的底物募集亚基。在fwd-1突变株中，FRQ降解缺陷，导致过度磷酸化FRQ的积累和昼夜节律的丧失。CSN（COP 9信号体）促进SCF复合物在体内的功能。但在体外，CSN对cullin的去脱氧抑制SCF活性。在脉孢菌中，csn-2亚基的破坏损害FRQ降解并损害正常的昼夜节律功能。这些缺陷是由于csn-2突变体中FWD-1的水平急剧降低，这是其快速降解的结果。SCFFWD-1复合物的其它组分SKP-1和CUL-1在突变体中也不稳定。这些结果确立了SCFFWD-1和CSN在脉孢菌生物钟中的重要作用，并表明它们是真核生物生物钟的保守组成部分。此外，这些发现解决了CSN悖论，并表明CSN的主要功能是维持SCF泛素连接酶在体内的稳定性。
Phosphorylation of the Neurospora circadian clock protein FREQUENCY (FRQ) promotes its degradation through the ubiquitin-proteasome pathway. Ubiquitination of FRQ requires FWD-1 (F-box/WD-40 repeat-containing protein-1), which is the substrate-recruiting subunit of an SCF (SKP/Cullin/F-box)-type ubiquitin ligase. in the fwd-1 mutant strains, FRQ degradation is defective, resulting in the accumulation of hyperphosphorylated FRQ and the loss of the circadian rhythmicities. The CSN (COP9 signalosome) promotes the function of SCF complexes in vivo. But in vitro, deneddylation of cullins by CSN inhibits SCF activity. In Neurospora, the disruption of the csn-2 subunit impairs FRQ degradation and compromises the normal circadian functions. These defects are due to the dramatically reduced levels of FWD-1 in the csn-2 mutant, a result of its rapid degradation. other components of the SCFFWD-1 complex, SKP-1 and CUL-1 are also unstable in the mutant. These results establish important roles for SCFFWD-1 and CSN in the circadian clock of Neurosporo and suggest that they are conserved components of the eukaryotic circadian clocks. in addition, these findings resolve the CSN paradox and suggest that the major function of CSN is to maintain the stability of SCF ubiquitin ligases in vivo.