Deubiquitinases: key regulators of the circadian clock

Abstract

All living organisms experience daily environmental cycles and have consequently evolved to synchronize and adapt to this changing environment. Biological processes such as hormonal secretion, body temperature and sleep follow daily cycles called circadian rhythms that are driven by a molecular clock running in most cells and tissues of the body. This clock is composed of transcriptional-translational negative feedback loops involving clock genes and proteins. This molecular mechanism functions with a period of ~24 hours, and it promotes daily rhythms in the expression of numerous genes. For this robust mechanism to function, the abundance and activity of clock proteins need to be tightly regulated. One of the mechanisms by which this can be achieved is ubiquitination. Indeed, many ubiquitin ligases can tag core clock proteins in order to target them for proteasomal degradation. However, deubiquitinases can reverse this process by removing or modifying these ubiquitin signals and are thus important enzymes in clock protein homeostasis and regulation. Recent studies on the mammalian and Drosophila clock mechanisms have identified a number of deubiquitinases able to stabilize core clock proteins, change their cellular localization or even regulate their activity. In this review, we aim to discuss the fundamental roles of ubiquitination and deubiquitination in the circadian clock by presenting all deubiquitinases found to be involved in circadian rhythms in the aim to give a global view of recent advances in this emerging field.

In Cerebellar Atrophy of 12-Month-Old ATM-Null Mice, Transcriptome Upregulations Concern Most Neurotransmission and Neuropeptide Pathways, While Downregulations Affect Prominently Itpr1, Usp2 and Non-Coding RNA

“…USP2-null mice show impaired motor coordination and balance [174], so its deficiency in an ATM-null cerebellum might contribute to ataxia pathogenesis. This deubiquitinase is also known as a regulator of circadian clock components [175], and indeed several USP2 effectors also showed deficient transcript levels, such as Cry1 and Cry2. In view of the role of KAT5 for the regulation of ATM activity, it may also be relevant that a transcript reduction in our dataset was observed for the KAT5-dependent kinase Chka, which is responsible for phospholipid biosynthesis [176,177].…”

REV-ERBα negatively regulates NLRP6 transcription and reduces the severity of Salmonella infection in mice

“…The circadian clock is present in almost all living organisms, allowing the anticipation of daily environmental changes and promoting optimal physiological function [ 3 ]. In higher organisms such as mammals, almost all aspects of physiology are regulated under circadian control, including sleep–wake cycles, blood pressure, hormonal levels, and metabolic and immune functions [ 4 ]. At the molecular level, the circadian clock machinery comprises transcriptional activators, including circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), operating together as a heterodimer that activates the transcription of clock-controlled genes.…”