scholarly journals CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch

2018 ◽  
Vol 115 (23) ◽  
pp. 5986-5991 ◽  
Author(s):  
Rajesh Narasimamurthy ◽  
Sabrina R. Hunt ◽  
Yining Lu ◽  
Jean-Michel Fustin ◽  
Hitoshi Okamura ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Splice Variant ◽  
Carboxyl Terminus ◽  
Casein Kinase 1 ◽  
Multisite Phosphorylation ◽  
Period 2 ◽  
Cellular Environment ◽  
Clock Component ◽  
Biophysical Analysis ◽  
Carboxyl Terminal

Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by casein kinase 1 (CK1), an essential clock component that is conserved from algae to humans. These subsequent phosphorylations stabilize PER2, delay its degradation, and lengthen the period of the circadian clock. Here, we perform a comprehensive biochemical and biophysical analysis of mouse PER2 (mPER2) priming phosphorylation and demonstrate, surprisingly, that CK1δ/ε is indeed the priming kinase. We find that both CK1ε and a recently characterized CK1δ2 splice variant more efficiently prime mPER2 for downstream phosphorylation in cells than the well-studied splice variant CK1δ1. While CK1 phosphorylation of PER2 was previously shown to be robust to changes in the cellular environment, our phosphoswitch mathematical model of circadian rhythms shows that the CK1 carboxyl-terminal tail can allow the period of the clock to be sensitive to cellular signaling. These studies implicate the extreme carboxyl terminus of CK1 as a key regulator of circadian timing.

scholarly journals Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein and ubiquitin ligase MDM2

2018 ◽  
Vol 11 (556) ◽  
pp. eaau0715 ◽  
Author(s):  
JingJing Liu ◽  
Xianlin Zou ◽  
Tetsuya Gotoh ◽  
Anne M. Brown ◽  
Liang Jiang ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Ubiquitin Ligase ◽  
Posttranslational Modifications ◽  
Mammalian Cells ◽  
Tumor Development ◽  
Mouse Double Minute ◽  
Period 2 ◽  
Clock Component ◽  
Ubiquitin Ligase Complex ◽  
Double Minute

The circadian clock relies on posttranslational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD 2 (PER2) is mediated by its phospho-specific recognition by β-transducin repeat–containing proteins (β-TrCPs), which are F-box–containing proteins that function as substrate recognition subunits of the SCFβ-TRCPubiquitin ligase complex. However, this mode of regulating PER2 stability falls short of explaining the persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery. We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation. Deregulation of MDM2 plays a major role in oncogenesis by contributing to the accumulation of genomic and epigenomic alterations that favor tumor development. MDM2-mediated PER2 turnover was important for defining the circadian period length in mammalian cells, a finding that emphasizes the connection between the circadian clock and cancer. Our results not only broaden the range of specific substrates of MDM2 beyond the cell cycle to include circadian components but also identify a previously unknown regulator of the clock as a druggable node that is often found to be deregulated during tumorigenesis.

scholarly journals Cyclin-dependent kinase 5 (CDK5) regulates the circadian clock

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Andrea Brenna ◽  
Iwona Olejniczak ◽  
Rohit Chavan ◽  
Jürgen A Ripperger ◽  
Sonja Langmesser ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Cyclin Dependent Kinase ◽  
Suprachiasmatic Nuclei ◽  
Nuclear Entry ◽  
Period 2 ◽  
Clock Component ◽  
Free Running ◽  
Free Running Period ◽  
Cryptochrome 1 ◽  
Cyclin Dependent Kinase 5

Circadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here, we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Of note is that CDK5 may not exclusively phosphorylate PER2, but in addition may regulate other proteins that are involved in the clock mechanism. Taken together, it appears that CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by a derailed circadian clock.

scholarly journals Cyclin Dependent Kinase 5 (CDK5) Regulates the Circadian Clock

2019 ◽  
Author(s):  
Andrea Brenna ◽  
Iwona Olejniczak ◽  
Rohit Chavan ◽  
Jürgen A. Ripperger ◽  
Sonja Langmesser ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Cyclin Dependent Kinase ◽  
Suprachiasmatic Nuclei ◽  
Nuclear Entry ◽  
Period 2 ◽  
Clock Component ◽  
Free Running ◽  
Free Running Period ◽  
Cryptochrome 1 ◽  
Cyclin Dependent Kinase 5

AbstractCircadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Therefore, CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by the circadian clock.

scholarly journals Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation

2021 ◽  
Vol 22 (7) ◽  
pp. 3787
Author(s):  
Hussam Ibrahim ◽  
Philipp Reus ◽  
Anna Katharina Mundorf ◽  
Anna-Lena Grothoff ◽  
Valerie Rudenko ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Transcriptional Repression ◽  
Small Gtpase ◽  
Main Role ◽  
Interacting Proteins ◽  
Casein Kinase 1 ◽  
Bona Fide ◽  
Kinetics Of

Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.

scholarly journals Circadian clock protein Rev-erbα regulates neuroinflammation

2019 ◽  
Vol 116 (11) ◽  
pp. 5102-5107 ◽  
Author(s):  
Percy Griffin ◽  
Julie M. Dimitry ◽  
Patrick W. Sheehan ◽  
Brian V. Lananna ◽  
Chun Guo ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Microglial Activation ◽  
Time Of Day ◽  
Resting State Functional Connectivity ◽  
Promoter Regions ◽  
Clock Component ◽  
Glial Cultures ◽  
Inflammatory Phenotype

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα−/− mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα−/− mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα−/− microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB–related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα−/− mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα–deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα−/− mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

scholarly journals Machine Learning Helps Identify CHRONO as a Circadian Clock Component

PLoS Biology ◽  
2014 ◽  
Vol 12 (4) ◽  
pp. e1001840 ◽  
Author(s):  
Ron C. Anafi ◽  
Yool Lee ◽  
Trey K. Sato ◽  
Anand Venkataraman ◽  
Chidambaram Ramanathan ◽  
...  
Keyword(s):  
Machine Learning ◽  
Circadian Clock ◽  
Clock Component

scholarly journals ABA signalling is regulated by the circadian clock component LHY

2018 ◽  
Vol 220 (3) ◽  
pp. 661-663 ◽  
Author(s):  
Fiona E. Belbin ◽  
Antony N. Dodd
Keyword(s):  
Circadian Clock ◽  
Clock Component

scholarly journals EARLY FLOWERING 3 controls temperature responsiveness of the circadian clock

2020 ◽  
Author(s):  
Zihao Zhu ◽  
Marcel Quint ◽  
Muhammad Usman Anwer
Keyword(s):  
Circadian Clock ◽  
Biological Rhythms ◽  
Early Flowering ◽  
Climate Change Scenarios ◽  
Temperature Changes ◽  
Physiological Processes ◽  
Average Global Temperature ◽  
Clock Component ◽  
Rhythmic Growth

SummaryPredictable changes in light and temperature during a diurnal cycle are major entrainment cues that enable the circadian clock to generate internal biological rhythms that are synchronized with the external environment. With the average global temperature predicted to keep increasing, the intricate light-temperature coordination that is necessary for clock functionality is expected to be seriously affected. Hence, understanding how temperature signals are perceived by the circadian clock has become an important issue, especially in light of climate change scenarios. In Arabidopsis, the clock component EARLY FLOWERING 3 (ELF3) not only serves as an essential light Zeitnehmer, but also functions as a thermosensor participating in thermomorphogenesis. However, the role of ELF3 in temperature entrainment of the circadian clock is not fully understood. Here, we report that ELF3 is essential for delivering temperature input to the clock. We demonstrate that in the absence of ELF3, the oscillator was unable to properly respond to temperature changes, resulting in an impaired gating of thermoresponses. Consequently, clock-controlled physiological processes such as rhythmic growth and cotyledon movement were disturbed. Together, our results reveal that ELF3 is an essential Zeitnehmer for temperature sensing of the oscillator, and thereby for coordinating the rhythmic control of thermoresponsive physiological outputs.

scholarly journals Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases

2020 ◽  
Vol 6 (38) ◽  
pp. eabc0418
Author(s):  
Chatrin Chatrin ◽  
Mads Gabrielsen ◽  
Lori Buetow ◽  
Mark A. Nakasone ◽  
Syed F. Ahmed ◽  
...  
Keyword(s):  
Cross Talk ◽  
Posttranslational Modifications ◽  
Unknown Function ◽  
Carboxyl Terminus ◽  
Structural Studies ◽  
Future Studies ◽  
Adp Ribosylation ◽  
Carboxyl Terminal ◽  
Adp Ribosyltransferase ◽  
Structural Insights

Cellular cross-talk between ubiquitination and other posttranslational modifications contributes to the regulation of numerous processes. One example is ADP-ribosylation of the carboxyl terminus of ubiquitin by the E3 DTX3L/ADP-ribosyltransferase PARP9 heterodimer, but the mechanism remains elusive. Here, we show that independently of PARP9, the conserved carboxyl-terminal RING and DTC (Deltex carboxyl-terminal) domains of DTX3L and other human Deltex proteins (DTX1 to DTX4) catalyze ADP-ribosylation of ubiquitin’s Gly76. Structural studies reveal a hitherto unknown function of the DTC domain in binding NAD+. Deltex RING domain recruits E2 thioesterified with ubiquitin and juxtaposes it with NAD+ bound to the DTC domain to facilitate ADP-ribosylation of ubiquitin. This ubiquitin modification prevents its activation but is reversed by the linkage nonspecific deubiquitinases. Our study provides mechanistic insights into ADP-ribosylation of ubiquitin by Deltex E3s and will enable future studies directed at understanding the increasingly complex network of ubiquitin cross-talk.

Sign in / Sign up

Export Citation Format

Share Document