scholarly journals Differential effects of SUMO1 and SUMO2 on circadian protein PER2 stability and function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ling-Chih Chen ◽  
Yung-Lin Hsieh ◽  
Grace Y. T. Tan ◽  
Tai-Yun Kuo ◽  
Yu-Chi Chou ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Regulatory System ◽  
Casein Kinase 1 ◽  
Suppressor Function ◽  
Clock Proteins ◽  
Transcriptional Suppression ◽  
Circadian Clock Proteins ◽  
And Function ◽  
Protein Oscillation ◽  
Transcriptional Suppressor

AbstractPosttranslational modification (PTM) of core circadian clock proteins, including Period2 (PER2), is required for proper circadian regulation. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs or their interaction with PER2 phosphorylation. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had different effects on PER2 turnover and transcriptional suppressor function. SUMO2 conjugation facilitated PER2 interaction with β-TrCP leading to PER2 proteasomal degradation. In contrast, SUMO1 conjugation, mediated by E3 SUMO-protein ligase RanBP2, enhanced CK1-mediated PER2S662 phosphorylation, inhibited PER2 degradation and increased PER2 transcriptional suppressor function. PER2 K736 was critical for both SUMO1- and SUMO2-conjugation. A PER2K736R mutation was sufficient to alter PER2 protein oscillation and reduce PER2-mediated transcriptional suppression. Together, our data revealed that SUMO1 versus SUMO2 conjugation acts as a determinant of PER2 stability and function and thereby affects the circadian regulatory system and the expression of clock-controlled genes.

scholarly journals Differential Effects of SUMO1/2 on Circadian Protein PER2 Stability and Function

2019 ◽  
Author(s):  
Ling-Chih Chen ◽  
Yung-Lin Hsieh ◽  
Tai-Yun Kuo ◽  
Yu-Chi Chou ◽  
Pang-Hung Hsu ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Regulatory System ◽  
Casein Kinase 1 ◽  
Circadian Periodicity ◽  
Suppressor Function ◽  
Clock Proteins ◽  
Transcriptional Suppression ◽  
Circadian Clock Proteins ◽  
And Function ◽  
Transcriptional Suppressor

AbstractPosttranslational modification (PTM) of core circadian clock proteins, including Period2 (PER2), is required for proper circadian regulation. PER2 function is regulated by casein kinase 1 (CK1)-mediated phosphorylation and ubiquitination but little is known about other PER2 PTMs or their interaction with PER2 phosphorylation. We found that PER2 can be SUMOylated by both SUMO1 and SUMO2; however, SUMO1 versus SUMO2 conjugation had different effects on PER2 turnover and transcriptional suppressor function. SUMO2 conjugation facilitated PER2-β-TrCP interaction leading to PER2 proteasomal degradation. In contrast, SUMO1 conjugation, mediated by E3 SUMO-protein ligase RanBP2, enhanced CK1-mediated PER2S662 phosphorylation and increased PER2 transcriptional suppressor function. PER2 K736 was critical for both SUMO1- and SUMO2-conjugation. A PER2K736R mutation was sufficient to alter circadian periodicity and reduce PER2-mediated transcriptional suppression. Together, our data revealed SUMO1 versus SUMO2 conjugation acts as an upstream determinant of PER2 phosphorylation and thereby affects the circadian regulatory system and circadian periodicity.

Going green with solar-powered ILC3 homeostasis

2019 ◽  
Vol 4 (40) ◽  
pp. eaaz0433
Author(s):  
Kyle Burrows ◽  
Arthur Mortha
Keyword(s):  
Circadian Clock ◽  
Link Type ◽  
Clock Proteins ◽  
Circadian Clock Proteins ◽  
Solar Powered ◽  
And Function

Circadian clock proteins BMAL1 and REV-ERBα harmonize the development and function of ILC3 (see related articles by Teng et al. and Wang et al.).

Tissue-specific peptide pools. Generation and function

2000 ◽  
Vol 72 (3) ◽  
pp. 355-363 ◽  
Author(s):  
Vadim T. Ivanov ◽  
Oleg N. Yatskin ◽  
Olga A. Kalinina ◽  
Marina M. Philippova ◽  
Andrei A. Karelin ◽  
...  
Keyword(s):  
Surrounding Medium ◽  
Regulatory System ◽  
Systematic Analysis ◽  
Tissue Specific ◽  
Tissue Extracts ◽  
Normal Ratio ◽  
And Function ◽  
Dying Cells ◽  
Specific Peptide

Systematic analysis of several tissue extracts for peptide components followed by bioactivity studies leads to formulation of the concept of "tissue-specific peptide pools". According to that concept the endogenous proteolysis of proteins with well-established functions, such as hemoglobin, actin, and cellular enzymes in tissues leads to formation of the sets (or pools) of bioactive peptides. The sets are tissue-specific on one hand and conservative in a given tissue at normal conditions on the other. The content and the composition of pool components are sensitive both to pathologies linked with alterations of tissue metabolism and to prolonged physiological changes. In vivo formation of fragments of functional proteins includes several consecutive proteolytic stages inside the cells and further release of bioactive compounds into the surrounding medium. The effects of pool components take place predominantly at tissue and cellular levels, their effects being related to stimulation or inhibition of cell growth, induction of cell differentiation, and death. The above-mentioned features lead to the proposal that the main in vivo function of components of tissue-specific peptides is maintenance of tissue homeostasis, i.e., the normal ratio of functional, dividing, differentiating, and dying cells of tissues. Components of tissue-specific peptide pools display several features distinguishing them from "classical" peptide hormones and neuromediators. Summarizing, a novel peptidergic regulatory system is considered.

scholarly journals Circadian Clock Proteins in Prokaryotes: Hidden Rhythms?

2010 ◽  
Vol 1 ◽  
Author(s):  
Maria Loza-Correa ◽  
Laura Gomez-Valero ◽  
Carmen Buchrieser
Keyword(s):  
Circadian Clock ◽  
Clock Proteins ◽  
Circadian Clock Proteins

scholarly journals Attenuated SIRT1 Activity Leads to PER2 Cytoplasmic Localization and Dampens the Amplitude of Bmal1 Promoter-Driven Circadian Oscillation

2021 ◽  
Vol 15 ◽  
Author(s):  
Atsushige Ashimori ◽  
Yasukazu Nakahata ◽  
Toshiya Sato ◽  
Yuichiro Fukamizu ◽  
Takaaki Matsui ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Circadian Clock ◽  
Posttranslational Modifications ◽  
Cultured Cells ◽  
Circadian Oscillation ◽  
Clock Proteins ◽  
Circadian Clock Proteins ◽  
Circadian Physiology ◽  
And Behavior ◽  
Robust Systems

The circadian clock possesses robust systems to maintain the rhythm approximately 24 h, from cellular to organismal levels, whereas aging is known to be one of the risk factors linked to the alternation of circadian physiology and behavior. The amount of many metabolites in the cells/body is altered with the aging process, and the most prominent metabolite among them is the oxidized form of nicotinamide adenine dinucleotide (NAD+), which is associated with posttranslational modifications of acetylation and poly-ADP-ribosylation status of circadian clock proteins and decreases with aging. However, how low NAD+ condition in cells, which mimics aged or pathophysiological conditions, affects the circadian clock is largely unknown. Here, we show that low NAD+ in cultured cells promotes PER2 to be retained in the cytoplasm through the NAD+/SIRT1 axis, which leads to the attenuated amplitude of Bmal1 promoter-driven luciferase oscillation. We found that, among the core clock proteins, PER2 is mainly affected in its subcellular localization by NAD+ amount, and a higher cytoplasmic PER2 localization was observed under low NAD+ condition. We further found that NAD+-dependent deacetylase SIRT1 is the regulator of PER2 subcellular localization. Thus, we anticipate that the altered PER2 subcellular localization by low NAD+ is one of the complex changes that occurs in the aged circadian clock.

scholarly journals Inhibition of O-GlcNAc Transferase Alters the Differentiation and Maturation Process of Human Monocyte Derived Dendritic Cells

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3312
Author(s):  
Matjaž Weiss ◽  
Marko Anderluh ◽  
Martina Gobec
Keyword(s):  
Dendritic Cells ◽  
Posttranslational Modification ◽  
Human Monocyte ◽  
T Cell Differentiation ◽  
Maturation Process ◽  
Hla Dr ◽  
Glcnac Transferase ◽  
And Function

The O-GlcNAcylation is a posttranslational modification of proteins regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase. These enzymes regulate the development, proliferation and function of cells, including the immune cells. Herein, we focused on the role of O-GlcNAcylation in human monocyte derived dendritic cells (moDCs). Our study suggests that inhibition of OGT modulates AKT and MEK/ERK pathways in moDCs. Changes were also observed in the expression levels of relevant surface markers, where reduced expression of CD80 and DC-SIGN, and increased expression of CD14, CD86 and HLA-DR occurred. We also noticed decreased IL-10 and increased IL-6 production, along with diminished endocytotic capacity of the cells, indicating that inhibition of O-GlcNAcylation hampers the transition of monocytes into immature DCs. Furthermore, the inhibition of OGT altered the maturation process of immature moDCs, since a CD14medDC-SIGNlowHLA-DRmedCD80lowCD86high profile was noticed when OGT inhibitor, OSMI-1, was present. To evaluate DCs ability to influence T cell differentiation and polarization, we co-cultured these cells. Surprisingly, the observed phenotypic changes of mature moDCs generated in the presence of OSMI-1 led to an increased proliferation of allogeneic T cells, while their polarization was not affected. Taken together, we confirm that shifting the O-GlcNAcylation status due to OGT inhibition alters the differentiation and function of moDCs in in vitro conditions.

scholarly journals 2PT229 The regulation of cyanobacterial circadian clock proteins KaiB-KaiC interaction by ATP(The 50th Annual Meeting of the Biophysical Society of Japan)

2012 ◽  
Vol 52 (supplement) ◽  
pp. S143
Author(s):  
Risa Mutoh ◽  
Atsuhito Nishimura ◽  
So Yasui ◽  
Kiyoshi Onai ◽  
Masahiro Ishiura
Keyword(s):  
Circadian Clock ◽  
Annual Meeting ◽  
Clock Proteins ◽  
Biophysical Society ◽  
Circadian Clock Proteins

scholarly journals The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells

2020 ◽  
Vol 4 (13) ◽  
pp. 3072-3084 ◽  
Author(s):  
Kamira Maharaj ◽  
John J. Powers ◽  
Alex Achille ◽  
Melanie Mediavilla-Varela ◽  
Wael Gamal ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Adverse Events ◽  
Safety Profile ◽  
Lymphocytic Leukemia ◽  
Casein Kinase 1 ◽  
Pi3k Inhibitors ◽  
Treg Number ◽  
Immune Mediated ◽  
And Function

Abstract The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Toxicities typical of this class of PI3K inhibitors are largely thought to be immune mediated, but they are poorly characterized. Here, we report the effects of idelalisib, duvelisib, and umbralisib on regulatory T cells (Tregs) on normal human T cells, T cells from CLL patients, and T cells in an Eμ-TCL1 adoptive transfer mouse CLL model. Ex vivo studies revealed differential effects of these PI3K inhibitors; only umbralisib treatment sustained normal and CLL-associated FoxP3+ human Tregs. Further, although all 3 inhibitors exhibit antitumor efficacy in the Eμ-TCL1 CLL model, idelalisib- or duvelisib-treated mice displayed increased immune-mediated toxicities, impaired function, and reduced numbers of Tregs, whereas Treg number and function were preserved in umbralisib-treated CLL-bearing mice. Finally, our studies demonstrate that inhibition of CK1ε can improve CLL Treg number and function. Interestingly, CK1ε inhibition mitigated impairment of CLL Tregs by PI3K inhibitors in combination treatment. These results suggest that the improved safety profile of umbralisib is due to its role as a dual PI3Kδ/CK1ε inhibitor that preserves Treg number and function.

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