title: Circadian modulation of proteasome activities and removal of carbonylated proteins.
abstract: The circadian clock generates rhythms with a periodicity of 24hours of various biochemical and physiological processes. Recent data suggest a mutual influence between the circadian clock and the cell cycle, and provide a functional connection between the circadian clock, cancer and ageing. In addition, the established link between the circadian clock and anti-oxidative defence suggests that elements of the redox homeostasis, including oxidized protein degradation pathways such as the proteasome, could be modulated by the circadian clock. Using HEK cells synchronized by a serum shock as an initial cellular model for studying the circadian influence on protein maintenance, we have shown that the level of carbonylated protein varies rhythmically following a 24hours period as well as the level of ROS. The proteasome also exhibits circadian rhythmicity in either its expression levels or activities. The rhythms match the circadian oscillations observed for protein oxidative damage. Moreover, adaptation to a Nrf2-dependent oxidative stress has been associated with an increase in the cellular capacity to degrade oxidized proteins that is attributable to an increased expression of the 20S proteasome and its activator Pa28αβ. Therefore, using our synchronized cellular models to investigate more precisely the modulation of proteasome function mediated by the circadian clock, we have shown that both Nrf2 and Pa28αβ exhibit a circadian expression. Interestingly, the circadian variation in ROS precedes the Nrf2 protein level and the transcript level of proteasome catalytic subunits and activators. If as we envisage, circadian rhythmicity is involved in damaged protein degradation, the age-associated alteration of the circadian system may therefore contribute to the accumulation of oxidized proteins and the decline of intracellular protein maintenance. Hence, strategies that could restore this vital function may be effective in slowing ageing and the onset of diseases for which a defect in the protein homeostasis has been proposed to play a key role.
authors.affiliation: Sorbonne Universités; UMR8256-UPMC-CNRS, ERL INSERM U1164 (Biological Adaptation and Ageing), Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Desvergne
authors.affiliation: Sorbonne Universités; UMR8256-UPMC-CNRS, ERL INSERM U1164 (Biological Adaptation and Ageing), Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ugarte
authors.affiliation: Sorbonne Universités; UMR8256-UPMC-CNRS, ERL INSERM U1164 (Biological Adaptation and Ageing), Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Petropoulos
authors.affiliation: Sorbonne Universités; UMR8256-UPMC-CNRS, ERL INSERM U1164 (Biological Adaptation and Ageing), Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet