To Ub or not to Ub: Regulation of circadian clocks by ubiquitination and deubiquitination

Abstract

Circadian clocks are internal timing systems that enable organisms to adjust their behavioral and physiological rhythms to the daily changes of their environment. These clocks generate self‐sustained oscillations at the cellular, tissue, and behavioral level. The rhythm‐generating mechanism is based on a gene expression network with a delayed negative feedback loop that causes the transcripts to oscillate with a period of approximately 24 hr. This oscillatory nature of the proteins involved in this network necessitates that they are intrinsically unstable, with a short half‐life. Hence, post‐translational modifications (PTMs) are important to precisely time the presence, absence, and interactions of these proteins at appropriate times of the day. Ubiquitination and deubiquitination are counter‐balancing PTMs which play a key role in this regulatory process. In this review, we take a comprehensive look at the roles played by the processes of ubiquitination and deubiquitination in the clock machinery of the most commonly studied eukaryotic models of the circadian clock: plants, fungi, fruit flies, and mammals. We present the effects exerted by ubiquitinating and deubiquitinating enzymes on the stability, but also the activity, localization, and interactions of clock proteins. Overall, these PTMs have key roles in regulating not only the pace of the circadian clocks but also their response to external cues and their control of cellular functions.

Role of circRNA in E3 Modification under Human Disease

“…In cells, deubiquitination enzymes work by removing ubiquitin tags from tagged proteins or reducing the length of polyubiquitin tags [ 49 ]. The balance between ubiquitination and deubiquitination affects physiological protein abundance and activity [ 61 ]. The critical role of the Lys48 and Lys63 linker chains in cell signaling has been well documented in many studies; in contrast to “atypical” chain types such as Lys6, Lys11, Lys27, Lys29, Lys33 or Met1, there are few reports, but a few studies have found that the physiological role of these atypical chains is also obvious [ 62 , 63 , 64 , 65 ].…”

Post-Translational Mechanisms of Plant Circadian Regulation

“…Numerous studies have shown that ubiquitination, occupies a prominent place in the turnover of circadian clock proteins [15]. Ubiquitination is a proteolytic pathway whereby targets are polyubiquitinated by covalent attachments of ubiquitin chains of 76 amino acid monomers which flag the substrate for cleavage into constituent amino acids, mediated by the 26S proteasome complex [16,17].…”

The involvement of host circadian clocks in the regulation of the immune response to parasitic infections in mammals

“…The timing and robustness of this circadian clockwork is aided by post-transcriptional and post-translational modifications mediated by many enzymes such as kinases, phosphatases, acetyl transferases, ubiquitin ligases, etc. 1,5 The circadian clockwork regulates various cellular and physiological processes via the control of the expression of clock-controlled genes (CCGs). Transcription factors such as CLOCK/BMAL1 or REV-ERBα bind numerous genes besides their targets within the clock.…”

“…These negative and positive feedback loops act temporally in such a manner that the transcripts and proteins encoded by many of the clock genes show a ~24‐h variation in their abundance. The timing and robustness of this circadian clockwork is aided by post‐transcriptional and post‐translational modifications mediated by many enzymes such as kinases, phosphatases, acetyl transferases, ubiquitin ligases, etc 1,5 …”