Protein Phosphatase 1 (PP1) Is a Post-Translational Regulator of the Mammalian Circadian Clock

Abstract

Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock.

The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1

“…However, if CK1δ/ε activity is disrupted, PER phosphorylation slows down, resulting in a slower oscillator (27,54,55). While our work was under review, Schmutz et al (39) showed that inhibition of PP1 activity slightly lengthened the period of bioluminescence and behavioral rhythms. The difference in the effect of PP1 inhibition may be due to different levels of inhibition and/or different methods of inhibition.…”

Increased Sensitivity of the Circadian System to Temporal Changes in the Feeding Regime of Spontaneously Hypertensive Rats - A Potential Role for Bmal2 in the Liver

“…The significant suppression of Pgc1α and Ppara expression may likely result in decreased levels of the PPARα/PGC1α transcriptional complex with nuclear receptors, which may consequently affect the activity of downstream genes regulating fatty acid uptake and oxidation in the liver of SHR maintained under RF. The other metabolism-relevant gene expression profiles in the liver did not differ between the two strains, namely that of Pparg (critical regulator of adipogenesis and osteogenesis [62,63]), Hdac3 (histone deacetylase integrating metabolic and circadian regulation [64,65]), Hif1a (the alpha subunit of the hypoxia inducible factor regulating homeostatic response to hypoxia [66]) and Ppp1r3c (a subunit of protein phosphatase 1 and major metabolic regulator linked to the circadian clock [67,68]). Thus, the data suggest that RF impacts the metabolic state in the liver of SHR differently than in Wistar rats, with the most obvious difference in the suppression of Pgc1α and Ppara expression and the imposition of a low-amplitude rhythmicity in Ppara and Prkab2 expression.…”

The intricate dance of post-translational modifications in the rhythm of life

“…2, state 2 to state 1). Inhibition of PPP1 in mouse suprachiasmatic nuclei lengthens the free-running period and alters light induced phase shifts 53 . PPP5 also regulates the circadian clock in culture by preventing autophosphorylation of CKI (ref.…”