Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2

Abstract

SummaryEndogenous 24-hour rhythms are generated by circadian clocks located in most tissues. The molecular clock mechanism is based on feedback loops involving clock genes and their protein products. Post-translational modifications, including ubiquitination, are important for regulating the clock feedback mechanism. Previous work has focused on the role of ubiquitin ligases in the clock mechanism. Here we show a role for the rhythmically-expressed deubiquitinating enzyme ubiquitin specific peptidase 2 (USP2) in clock function. Mice with a deletion of the Usp2 gene (Usp2 KO) display a longer free-running period of locomotor activity rhythms and altered responses of the clock to light. This was associated with altered expression of clock genes in synchronized Usp2 KO mouse embryonic fibroblasts and increased levels of clock protein PERIOD1 (PER1). USP2 can be coimmunoprecipitated with several clock proteins but directly interacts specifically with PER1 and deubiquitinates it. Interestingly, this deubiquitination does not alter PER1 stability. Taken together, our results identify USP2 as a new core component of the clock machinery and demonstrate a role for deubiquitination in the regulation of the circadian clock, both at the level of the core pacemaker and its response to external cues.

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure

“…Such a pattern of expression has been found at the mRNA level in any tissue analyzed, suggesting that USP2-45 plays a role in the rhythmic regulation of physiological processes everywhere in the organism (24,38,39). However, Usp2-KO mice show only relatively minor defects in the regulation of the circadian clock in general, as evidenced for example by the rhythmic control of behavior in running wheels (which we also carried out; data not shown) (46,56). It is therefore likely that the rhythmic levels of USP2-45 control diurnal expression of target proteins by stabilizing them.…”

Endogenous IL-1 in Cognitive Function and Anxiety: A Study in IL-1RI−/− Mice

“…Contrary to Goshen et al the animals we used for our study were not raised in reverse cycle, and we thus performed all our behavioural studies during their less active period. Interestingly, several studies have demonstrated the influence of sleep and time of day on hippocampal-dependent plasticity and subsequent behavioural abilities [34], [35], [36], [37]. In addition, a recent paper revealed that, under physiological conditions, time of day influenced IL-1β and IL-1RI expression and speculated that IL-1 may contribute to the basal functioning of the suprachiasmatic nucleus (SNC) clock [38].…”

Effects of sleep deprivation and aging on long-term and remote memory in mice

“…3A, two-way ANOVA for each, P , 0.05). SD also significantly decreased expression levels of Rbm3 and Hnrpdl (mRNA metabolism and trafficking (Kawamura et al 2002;Smart et al 2007)) and Usp2 (deubiquitination and control of circadian rhythms (Metzig et al 2011;Scoma et al 2011;Yang et al 2012)) ( Fig. 3B; two-way ANOVA for each, P , 0.05).…”