title: Circadian modulation of proteasome activity and accumulation of oxidized protein in human embryonic kidney HEK 293 cells and primary dermal fibroblasts.
abstract: The circadian system orchestrates the timing of physiological processes of an organism living in daily environmental changes. Disruption of circadian rhythmicity has been shown to result in increased oxidative stress and accelerated aging. The circadian regulation of antioxidant defenses suggests that other redox homeostasis elements such as oxidized protein degradation by the proteasome, could also be modulated by the circadian clock. Hence, we have investigated whether proteasome activities and oxidized protein levels would exhibit circadian rhythmicity in synchronized cultured mammalian cells and addressed the mechanisms underlying this process. Using synchronized human embryonic kidney HEK 293 cells and primary dermal fibroblasts, we have shown that the levels of carbonylated protein and proteasome activity vary rhythmically following a 24h period. Such a modulation of proteasome activity is explained, at least in part, by the circadian expression of both Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the proteasome activator PA28αβ. HEK 293 cells showed an increased susceptibility to oxidative stress coincident with the circadian-dependent lower activity of the proteasome. Finally, in contrast to young fibroblasts, no circadian modulation of the proteasome activity and carbonylated protein levels was evidenced in senescent fibroblasts. This paper reports a novel role of the circadian system for regulating proteasome function. In addition, the observation that proteasome activity is modulated by the circadian clock opens new avenues for both the cancer and the aging fields, as exemplified by the rhythmic resistance of immortalized cells to oxidative stress and loss of rhythmicity of proteasome activity in senescent fibroblasts.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, Biological Adaptation and Ageing-IBPS, F-75005 Paris, France; CNRS UMR-8256, F-75005 Paris, France; INSERM U1164, F-75005 Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Desvergne
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, Biological Adaptation and Ageing-IBPS, F-75005 Paris, France; CNRS UMR-8256, F-75005 Paris, France; INSERM U1164, F-75005 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ugarte
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, Biological Adaptation and Ageing-IBPS, F-75005 Paris, France; CNRS UMR-8256, F-75005 Paris, France; INSERM U1164, F-75005 Paris, France; LVMH Research, St. Jean de Braye, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Radjei
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, Biological Adaptation and Ageing-IBPS, F-75005 Paris, France; CNRS UMR-8256, F-75005 Paris, France; INSERM U1164, F-75005 Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Gareil
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, Biological Adaptation and Ageing-IBPS, F-75005 Paris, France; CNRS UMR-8256, F-75005 Paris, France; INSERM U1164, F-75005 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Petropoulos
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, Biological Adaptation and Ageing-IBPS, F-75005 Paris, France; CNRS UMR-8256, F-75005 Paris, France; INSERM U1164, F-75005 Paris, France. Electronic address: bertrand.friguet@upmc.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology; D000975:Antioxidants / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D050050:Protein Carbonylation / Q000235:genetics
chemical_list: D000975:Antioxidants; D009124:Muscle Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C085047:PSME1 protein, human; C486207:PSME2 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: Cellular aging; Circadian rhythmicity; HEK 293 cells; Human dermal fibroblasts; Nrf2; Oxidative stress; Proteasome; Proteasome activator PA28αβ; Protein oxidation