The circadian clock plays a critical role in regulating various physiological processes, including gene expression, metabolic regulation, immune response, and the sleep-wake cycle in living organisms. Post-translational modifications (PTMs) are crucial regulatory mechanisms to maintain the precise oscillation of the circadian clock. By modulating the stability, activity, cell localization and protein-protein interactions of core clock proteins, PTMs enable these proteins to respond dynamically to environmental and intracellular changes, thereby sustaining the periodic oscillations of the circadian clock. Different types of PTMs exert their effects through distincting molecular mechanisms, collectively ensuring the proper function of the circadian system. This review systematically summarized several major types of PTMs, including phosphorylation, acetylation, ubiquitination, SUMOylation and oxidative modification, and overviewed their roles in regulating the core clock proteins and the associated pathways, with the goals of providing a theoretical foundation for the deeper understanding of clock mechanisms and the treatment of diseases associated with circadian disruption.
Protein Processing, Post-Translational/physiology* ; Circadian Rhythm/physiology* ; Humans ; Animals ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Phosphorylation ; Acetylation ; Ubiquitination ; Sumoylation

The N-end rule pathway is a protein degradation pathway mediated by the ubiquitin-proteasome system, which specifically targets and degrades target proteins by recognizing specific residues at the N-terminus of the proteins. The residues which play a crucial role in the N-end rule pathway are called degrons, also known as N-degrons, as they are usually unstable at the N-terminal end of the protein. Currently, several N-end rule pathways have been identified in the eukaryotes, including the Arg/N-end rule, Ac/N-end rule, and Pro/N-end rule pathways, as well as the recently discovered Gly/N-end rule pathway. The Ac/N-end rule pathway targets proteins containing N-terminal acetylation (Nt-acetylation) residues. The Arg/N-end rule pathway, on the other hand, targets certain unacetylated residues and involves N-terminal arginylation. For proteins with N-terminal proline (Pro) and glycine (Gly) residues, they are neither modified by acetylation nor recognized through the Arg/N-end rule pathway. Therefore, these proteins are primarily recognized and degraded through the Pro/N-end rule pathway and the Gly/N-end rule pathway. The regulation of specific proteins through N-end rule pathway-mediated degradation plays an important role in numerous physiological and pathological processes, such as cardiovascular development, neurogenesis, meiosis, spermatogenesis, HPV infection, and cell apoptosis. In this review, we summarize the role and mechanisms of several known N-end rule pathways and discuss their relationship with certain diseases. As an independent protein degradation system, the N-end rule pathways still hold countless biological secrets waiting for exploring. The comprehensive understanding of these pathways could potentially uncover novel therapeutic targets for various diseases.
Humans ; Proteolysis ; Animals ; Proteasome Endopeptidase Complex/physiology* ; Acetylation ; Proteins/metabolism* ; Protein Processing, Post-Translational ; Ubiquitin/metabolism*

Human physiology and pathology can be affected by different nutritional conditions. At cellular level, the availability of a nutritional component not only mediates metabolic reactions but also transmits signals for diverse biological activities. Epigenetic regulation such as DNA methylation and histone post-translational modifications is considered as one of the nutrient-mediated signaling receivers as almost all of the epigenetic enzyme activities require intermediary metabolites as cofactors. The gut microbiome as “forgotten organ” has been suggested as a metabolite generator as well as a nutrient sensor for its host organism, affecting human health and diseases. Given the metabolite-dependent activities of epigenetic regulators, the gut microbiome has a high potential to influence the epigenetics in human physiology. Here, I review the involvement of gut microbiome in diverse human diseases and the mechanisms of epigenetic regulation by different metabolites. Thereafter, I discuss how the gut microbiome-generated metabolites affect host epigenetics, raising a possibility to develop a therapeutic intervention based on the interaction between the microbiome and epigenetics for human health.
DNA Methylation ; Epigenomics* ; Gastrointestinal Microbiome* ; Histones ; Humans* ; Metabolism ; Microbiota ; Pathology ; Physiology ; Protein Processing, Post-Translational

The innate immune response against viral infection is mainly relies on type I interferon, the production of which is mediated by TANK-binding kinase 1 (TBK1). It is revealed that the downstream TBK1 is activated by viral nucleic acid sensors RIG-I, cGAS and TLR3. The activity of TBK1 is complexly and precisely regulated by different type of protein modifications, including phosphorylation, ubiquitination and Sumolylation. This article focuses on the role of TBK1 in anti-viral innate immunity and the regulatory mechanism for the TBK1 activation.
Humans ; Immunity, Innate ; genetics ; physiology ; Interferon Type I ; Phosphorylation ; Protein Processing, Post-Translational ; immunology ; Protein-Serine-Threonine Kinases ; chemistry ; physiology ; Signal Transduction ; Ubiquitination ; Virus Diseases ; physiopathology

Influenza C virus, a member of the Orthomyxoviridae family, causes flu-like disease but typically only with mild symptoms. Humans are the main reservoir of the virus, but it also infects pigs and dogs. Very recently, influenza C-like viruses were isolated from pigs and cattle that differ from classical influenza C virus and might constitute a new influenza virus genus. Influenza C virus is unique since it contains only one spike protein, the hemagglutinin-esterase-fusion glycoprotein HEF that possesses receptor binding, receptor destroying and membrane fusion activities, thus combining the functions of Hemagglutinin (HA) and Neuraminidase (NA) of influenza A and B viruses. Here we briefly review the epidemiology and pathology of the virus and the morphology of virus particles and their genome. The main focus is on the structure of the HEF protein as well as on its co- and post-translational modification, such as N-glycosylation, disulfide bond formation, S-acylation and proteolytic cleavage into HEF1 and HEF2 subunits. Finally, we describe the functions of HEF: receptor binding, esterase activity and membrane fusion.
Animals ; Cattle ; Dogs ; Hemagglutinins, Viral ; chemistry ; metabolism ; Influenzavirus C ; physiology ; Orthomyxoviridae Infections ; metabolism ; virology ; Protein Conformation ; Protein Folding ; Protein Processing, Post-Translational ; Viral Fusion Proteins ; chemistry ; metabolism

Post-translational modifications (PTMs) of transcription factors play a crucial role in regulating metabolic homeostasis. These modifications include phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, and O-GlcNAcylation. Recent studies have shed light on the importance of lysine acetylation at nonhistone proteins including transcription factors. Acetylation of transcription factors affects subcellular distribution, DNA affinity, stability, transcriptional activity, and current investigations are aiming to further expand our understanding of the role of lysine acetylation of transcription factors. In this review, we summarize recent studies that provide new insights into the role of protein lysine-acetylation in the transcriptional regulation of metabolic homeostasis.
Acetylation ; Animals ; Diabetes Mellitus, Type 2 ; metabolism ; Homeostasis ; genetics ; physiology ; Humans ; Protein Processing, Post-Translational ; genetics ; physiology ; Transcription Factors ; metabolism

Histone methylation is one of the most widely studied post-transcriptional modifications. It is thought to be an important epigenetic event that is closely associated with cell fate determination and differentiation. To explore the spatiotemporal expression of histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 trimethylation (H3K27me3) epigenetic marks and methylation or demethylation transferases in tooth organ development, we measured the expression of SET7, EZH2, KDM5B and JMJD3 via immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis in the first molar of BALB/c mice embryos at E13.5, E15.5, E17.5, P0 and P3, respectively. We also measured the expression of H3K4me3 and H3K27me3 with immunofluorescence staining. During murine tooth germ development, methylation or demethylation transferases were expressed in a spatial-temporal manner. The bivalent modification characterized by H3K4me3 and H3K27me3 can be found during the tooth germ development, as shown by immunofluorescence. The expression of SET7, EZH2 as methylation transferases and KDM5B and JMJD3 as demethylation transferases indicated accordingly with the expression of H3K4me3 and H3K27me3 respectively to some extent. The bivalent histone may play a critical role in tooth organ development via the regulation of cell differentiation.
Animals ; Cell Differentiation ; physiology ; DNA-Binding Proteins ; analysis ; Dental Papilla ; embryology ; Embryo, Mammalian ; Enamel Organ ; embryology ; Enhancer of Zeste Homolog 2 Protein ; Epigenesis, Genetic ; physiology ; Gene Expression Regulation, Developmental ; Histone-Lysine N-Methyltransferase ; analysis ; Histones ; metabolism ; Jumonji Domain-Containing Histone Demethylases ; analysis ; Lysine ; metabolism ; Methylation ; Mice ; Mice, Inbred BALB C ; Odontogenesis ; physiology ; Polycomb Repressive Complex 2 ; analysis ; Protein Processing, Post-Translational ; physiology ; Tooth Germ ; embryology

By means of a circadian clock system, all the living organisms on earth including human beings can anticipate the environmental rhythmic changes such as light/dark and warm/cold periods in a daily as well as in a yearly manner. Anticipating such environmental changes provide organisms with survival benefits via manifesting behavior and physiology at an advantageous time of the day and year. Cell-autonomous circadian oscillators, governed by transcriptional feedback loop composed of positive and negative elements, are organized into a hierarchical system throughout the organisms and generate an oscillatory expression of a clock gene by itself as well as clock controlled genes (ccgs) with a 24 hr periodicity. In the feedback loop, hetero-dimeric transcription factor complex induces the expression of negative regulatory proteins, which in turn represses the activity of transcription factors to inhibit their own transcription. Thus, for robust oscillatory rhythms of the expression of clock genes as well as ccgs, the precise control of subcellular localization and/or timely translocation of core clock protein are crucial. Here, we discuss how sub-cellular localization and nuclear translocation are controlled in a time-specific manner focusing on the negative regulatory clock proteins.
Circadian Clocks* ; Circadian Rhythm ; CLOCK Proteins ; Humans ; Periodicity ; Phosphorylation ; Physiology ; Protein Processing, Post-Translational ; Repressor Proteins* ; Transcription Factors

The phosphorylation is one of most common protein post-translational modifications. The protein phosphorylation plays important roles in the life through the reversible process of phosphorylation and dephosphorylation by kinases and phosphatases. Systematical analysis of the phosphorylation state of proteins would greatly help to reveal the mystery of the life. Recently, with the development of mass spectrometer, bioinformatics sortwares and enrichment methods of phosphopeptides, phosphorylation stduy of orgnism proteins by mass spectrometer has become mature gradually. Liver is one of the most important metabolic and immune organs. In-depth study of protein phosphorylation in liver is of great importance to reveal its function. And booming phosphoproteomics has been applied into the study of liver, which has deepened the knowledge of molecular mechnism of its physiology and pathology states. Here, we review the recent progress on the research and development of phosphoproteomics and their application in liver proteomics study.
Computational Biology ; Humans ; Liver ; metabolism ; pathology ; physiology ; Mass Spectrometry ; Phosphopeptides ; metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Proteomics

As a critical tumor suppressor, p53 is inactivated in human cancer cells by somatic gene mutation or disruption of pathways required for its activation. Therefore, it is critical to elucidate the mechanism underlying p53 activation after genotoxic and cellular stresses. Accumulating evidence has indicated the importance of posttranslational modifications such as acetylation in regulating p53 stability and activity. However, the physiological roles of the eight identified acetylation events in regulating p53 responses remain to be fully understood. By employing homologous recombination, we introduced various combinations of missense mutations (lysine to arginine) into eight acetylation sites of the endogenous p53 gene in human embryonic stem cells (hESCs). By determining the p53 responses to DNA damage in the p53 knock-in mutant hESCs and their derivatives, we demonstrate physiological importance of the acetylation events within the core domain (K120 and K164) and at the C-terminus (K370/372/373/381/382/386) in regulating human p53 responses to DNA damage.
Acetylation ; Cells, Cultured ; DNA Damage ; Embryonic Stem Cells ; physiology ; Fibroblasts ; physiology ; Gene Expression Regulation ; Gene Knock-In Techniques ; Humans ; Protein Processing, Post-Translational ; Protein Stability ; Transcription, Genetic ; Tumor Suppressor Protein p53 ; physiology