The De-Ubiquitinylating Enzyme, USP2, Is Associated with the Circadian Clockwork and Regulates Its Sensitivity to Light

Abstract

We have identified a novel component of the circadian clock that regulates its sensitivity to light at the evening light to dark transition. USP2 (Ubiquitin Specific Protease 2), which de-ubiquitinylates and stabilizes target proteins, is rhythmically expressed in multiple tissues including the SCN. We have developed a knockout model of USP2 and found that exposure to low irradiance light at ZT12 increases phase delays of USP2−/− mice compared to wildtype. We additionally show that USP2b is in a complex with several clock components and regulates the stability and turnover of BMAL1, which in turn alters the expression of several CLOCK/BMAL1 controlled genes. Rhythmic expression of USP2 in the SCN and other tissues offers a new level of control of the clock machinery through de-ubiqutinylation and suggests a role for USP2 during circadian adaptation to environmental day length changes.

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.…”

“…As outlined in the introduction, Usp2 is controlled by the circadian timing system in numerous tissues, including the kidney (24,38,39). Thereby, the peak of expression of mRNA in mice in constant darkness (DD) is at Circadian Time 8 -12 and between ZT12 and 16 in the liver and kidney in LD (32,57), corresponding to the end of the subjective resting period (39,46). At the protein level, the diurnal expression of USP2-45 had been followed previously in the suprachiasmatic nucleus (SCN) and found to peak at ZT16 (46).…”

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).…”

CLOCK deubiquitylation by USP8 inhibits CLK/CYC transcription in Drosophila

“…Also notable is mammalian usp2; its mRNA cycles, and its transcription is under CLOCK/BMAL1 control (Oishi et al 2003(Oishi et al , 2005. USP2 was shown more recently to stabilize BMAL1 and CRY1 by deubiquitylation in mouse livers (Scoma et al 2011;Tong et al 2012). USP8/UBPY, another deubiquitylating enzyme in the USP family, functions in the endocytosis and endosome sorting of ligand-activated receptor tyrosine kinases (RTKs) in mammals (Mizuno et al 2005;Wright et al 2011), and a knockout of the usp8 gene causes developmental lethality in Drosophila as well as in mammals (Niendorf et al 2007;Mukai et al 2010).…”