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Southern African Journal of HIV Medicine 2021HIV is a chronic inflammatory state with the production of many acute-phase-reactant proteins. Some of these proteins have procoagulant activities that predispose...
BACKGROUND
HIV is a chronic inflammatory state with the production of many acute-phase-reactant proteins. Some of these proteins have procoagulant activities that predispose HIV-infected patients to thrombosis.
OBJECTIVES
The aim of the study was to evaluate the effects of HIV infection on the serum levels of C4b-binding protein (C4BP) and protein S as markers of predisposition to thrombosis in HIV-infected adults.
METHODS
The study population comprised of 61 HIV-infected adults on antiretroviral treatment (ART) who had achieved virological suppression, 58 HIV-infected adults not yet on ART and 59 HIV-negative healthy controls. The serum levels of free protein S, C4BP and the euglobulin clot lysis time (ECLT) were determined.
RESULTS
The mean plasma-free protein S level of HIV-infected patients on ART (86.9% ± 25.8%) was significantly higher than that of treatment-naïve HIV-infected patients (75.7% ± 27.3%) ( = 0.005). Conversely, there was no statistically significant difference between the protein S levels of the HIV-infected subjects on ART (86.9% ± 25.8%) and those of the controls (94.9% ± 7.9%) ( = 0.119). The mean C4BP was significantly higher in the treatment-naïve HIV-infected subjects (36.7 ± 1.7 ng/dL) than that in those on ART (30.7 ± 2.6 ng/dL) and that in the controls (22.4 ± 2.4 ng/dL) ( < 0.0001). Protein S deficiency was more prevalent among the subjects with elevated C4BP ( = 0.023). The mean ECLT was significantly more prolonged in the treatment-naïve HIV-infected subjects (241.9 ± 34.7 s) than controls (189.5 ± 40.7 s) (p < 0.0001).
CONCLUSION
HIV infection causes elevated levels of C4BP and diminishes the serum levels of free protein S. We infer that the risk of thrombosis (as measured by these biomarkers) decreases with the use of antiretroviral drugs.
PubMed: 34522427
DOI: 10.4102/sajhivmed.v22i1.1253 -
Journal of the American Chemical Society May 2020Per--acetylated unnatural monosaccharides containing a bioorthogonal group have been widely used for metabolic glycan labeling (MGL) in live cells for two decades, but...
Per--acetylated unnatural monosaccharides containing a bioorthogonal group have been widely used for metabolic glycan labeling (MGL) in live cells for two decades, but it is only recently that we discovered the existence of an artificial "S-glycosylation" between protein cysteines and per--acetylated sugars. While efforts are being made to avoid this nonspecific reaction in MGL, the reaction mechanism remains unknown. Here, we present a detailed mechanistic investigation, which unveils the "S-glycosylation" being an atypical glycosylation termed S-glyco-modification. In alkaline protein microenvironments, per--acetylated monosaccharides undergo base-promoted β-elimination to form thiol-reactive α,β-unsaturated aldehydes, which then react with cysteine residues via Michael addition. This S-glyco-modification produces 3-thiolated sugars in hemiacetal form, rather than typical glycosides. The elimination-addition mechanism guides us to develop 1,6-di--propionyl--azidoacetylgalactosamine (1,6-PrGalNAz) as an improved unnatural monosaccharide for MGL.
Topics: Glycosylation; Molecular Structure; Monosaccharides; Protein S
PubMed: 32339456
DOI: 10.1021/jacs.0c02110 -
Romanian Journal of Internal Medicine =... Dec 2020COVID-19 disease was associated with both thrombo-embolic events and in-situ thrombi formation in small vessels. Antiphospholipidic antibodies were found in some...
COVID-19 disease was associated with both thrombo-embolic events and in-situ thrombi formation in small vessels. Antiphospholipidic antibodies were found in some studies. Assessment of protein S activity in patients with COVID-19 as a cause of this prothrombotic state, and of the association of protein S activity with worse outcome. All patients admitted for COVID-19 disease in a university hospital between 15 of May and 15 of July 2020 were prospectively enrolled into this cohort study. Patients treated with antivitamin K anticoagulants and with liver disease were excluded. All patients had protein S activity determined at admission. The main outcome was survival, while secondary outcomes were clinical severity and lung damage. 91 patients were included, of which 21 (23.3%) died. Protein S activity was decreased in 65% of the patients. Death was associated with lower activity of protein S (median 42% vs. 58%, p < 0.001), and the association remained after adjustment for age, inflammation markers and ALAT. There was a dose-response relationship between protein S activity and clinical severity (Kendall_tau coefficient = -0.320, p < 0.001; Jonckheere-Terpstra for trend: p < 0.001) or pulmonary damage on CT scan (Kendall_tau coefficient = -0.290, p < 0.001; Jonckheere-Terpstra for trend: p < 0.001). High neutrophil count was also independently associated with death (p = 0.002). Protein S activity was lower in COVID-19 patients, and its level was associated with survival and disease severity, suggesting that it may have a role in the thrombotic manifestations of the disease.
Topics: COVID-19; Humans; Leukocyte Count; Lung; Neutrophils; Prospective Studies; Protein S; SARS-CoV-2; Severity of Illness Index; Survival Analysis; Thromboembolism; Tomography, X-Ray Computed
PubMed: 32841167
DOI: 10.2478/rjim-2020-0024 -
Frontiers in Neural Circuits 2023Alzheimer's disease (AD) is arguably the most common cause of dementia in the elderly and is marked by progressive synaptic degeneration, which in turn leads to... (Review)
Review
Alzheimer's disease (AD) is arguably the most common cause of dementia in the elderly and is marked by progressive synaptic degeneration, which in turn leads to cognitive decline. Studies in patients and in various AD models have shown that one of the early signatures of AD is neuronal hyperactivity. This excessive electrical activity contributes to dysregulated neural network function and synaptic damage. Mechanistically, evidence suggests that hyperexcitability accelerates production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that contribute to neural network impairment and synapse loss. This review focuses on the pathways and molecular changes that cause hyperexcitability and how RNS-dependent posttranslational modifications, represented predominantly by protein S-nitrosylation, mediate, at least in part, the deleterious effects of hyperexcitability on single neurons and the neural network, resulting in synaptic loss in AD.
Topics: Humans; Aged; Alzheimer Disease; Protein S; Neurons; Reactive Nitrogen Species
PubMed: 36817649
DOI: 10.3389/fncir.2023.1099467 -
Plant Science : An International... Jan 2024Salt stress is one of the major environmental stressors that remarkably hinders the processes of plant growth and development, thereby limiting crop productivity. An... (Review)
Review
Salt stress is one of the major environmental stressors that remarkably hinders the processes of plant growth and development, thereby limiting crop productivity. An understanding of the molecular mechanisms underlying plant responses against salinity stimulus will help guide the rational design of crop plants to counter these challenges. Nitric oxide (NO) is a redox-related signaling molecule regulating diverse biological processes in plant. Accumulating evidences indicated NO exert its biological functions through posttranslational modification of proteins, notably via S-nitrosylation. During the past decade, the roles of S-nitrosylation as a regulator of plant and S-nitrosylated candidates have also been established and detected. Emerging evidence indicated that protein S-nitrosylation is ubiquitously involved in the regulation of plant response to salt stress. However, little is known about this pivotal molecular amendment in the regulation of salt stress response. Here, we describe current understanding on the regulatory mechanisms of protein S-nitrosylation in response to salt stress in plants and highlight key challenges in this field.
Topics: Nitric Oxide; Plants; Plant Development; Salt Stress; Signal Transduction; Protein Processing, Post-Translational
PubMed: 37984610
DOI: 10.1016/j.plantsci.2023.111927 -
Current Neuropharmacology 2021Hydrogen sulfide (H2S) and hydrogen polysulfides are recognized as important signaling molecules that are generated physiologically in the body, including the central... (Review)
Review
Hydrogen sulfide (H2S) and hydrogen polysulfides are recognized as important signaling molecules that are generated physiologically in the body, including the central nervous system (CNS). Studies have shown that these two molecules are involved in cytoprotection against oxidative stress and inflammatory response. In the brain system, H2S and polysulfides exert multiple functions in both health and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), memory decline, and glioma. Mechanistically, S-Persulfidation (also known as S-sulfuration or S-sulfhydration) of target proteins is believed to be a fundamental mechanism that underlies H2S-regulated signaling pathways. Cysteine S-Persulfidation is an important paradigm of post translational protein modification in the process of H2S signaling. This model is established as a critical redox mechanism to regulate numerous biological functions, especially in H2S-mediated neuroprotection and neurogenesis. Although the current research of S-Persulfidation is still in its infancy, accumulative evidence suggests that protein S-Persulfidation may share similar characteristics with protein S-nitrosylation. In this review, we will provide a comprehensive insight into the S-Persulfidation biology of H2S and polysulfides in neurological ailments and presume potential avenues for therapeutic development in these disorders based on S-Persulfidation of target proteins.
Topics: Cysteine; Humans; Hydrogen Sulfide; Nervous System Diseases; Protein S; Sulfides
PubMed: 32888271
DOI: 10.2174/1570159X18666200905143550 -
Current Opinion in Chemical Biology Dec 2021Protein S-fatty acylation or S-palmitoylation is a reversible and regulated lipid post-translational modification (PTM) in eukaryotes. Loss-of-function mutagenesis... (Review)
Review
Protein S-fatty acylation or S-palmitoylation is a reversible and regulated lipid post-translational modification (PTM) in eukaryotes. Loss-of-function mutagenesis studies have suggested important roles for protein S-fatty acylation in many fundamental biological pathways in development, neurobiology, and immunity that are also associated with human diseases. However, the hydrophobicity and reversibility of this PTM have made site-specific gain-of-function studies more challenging to investigate. In this review, we summarize recent chemical biology approaches and methods that have enabled site-specific gain-of-function studies of protein S-fatty acylation and the investigation of the mechanisms and significance of this PTM in eukaryotic biology.
Topics: Acylation; Humans; Lipoylation; Protein Processing, Post-Translational; Protein S
PubMed: 34333222
DOI: 10.1016/j.cbpa.2021.06.004 -
Biochemical and Biophysical Research... Jan 2022Bi-oriented attachment of microtubules to the centromere is a pre-requisite for faithful chromosome segregation during mitosis. Budding yeast have point centromeres...
Bi-oriented attachment of microtubules to the centromere is a pre-requisite for faithful chromosome segregation during mitosis. Budding yeast have point centromeres containing the cis-element proteins CDE-I, -II, and -III, which interact with trans-acting factors such as Cbf1, Cse4, and Ndc10. Our previous genetic screens, using a comprehensive library of histone point mutants, revealed that the TBS-I, -II, and -III regions of nucleosomes are required for faithful chromosome segregation. In TBS-III deficient cells, peri-centromeric nucleosomes containing the H2A.Z homolog Htz1 are lacking, however, it is unclear why chromosome segregation is defective in these cells. Here, we show that, in cells lacking TBS-III, both chromatin binding at the centromere and the total amount of some of the centromere proteins are reduced, and transcription through the centromere is up-regulated during M-phase. Moreover, the chromatin binding of Cse4, Mif2, Cbf1, Ndc10, and Scm3 was reduced upon ectopic transcription through the centromere in wild-type cells. These results suggest that transcription through the centromere displaces key centromere proteins and, consequently, destabilizes the interaction between centromeres and microtubules, leading to defective chromosome segregation. The identification of new roles for histone binding residues in TBS-III will shed new light on nucleosome function during chromosome segregation.
Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Centromere; Centromere Protein A; Chromosomal Proteins, Non-Histone; Chromosome Segregation; DNA-Binding Proteins; Gene Expression Regulation, Fungal; Histones; Kinetochores; Microtubules; Mitosis; Models, Molecular; Nucleosomes; Protein Binding; Protein Conformation; Protein Isoforms; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription, Genetic
PubMed: 34844121
DOI: 10.1016/j.bbrc.2021.11.077 -
The Journal of Cell Biology Sep 2023The nuclear pore complex (NPC) physically interacts with chromatin and regulates gene expression. The Saccharomyces cerevisiae inner ring nucleoporin Nup170 has been...
The nuclear pore complex (NPC) physically interacts with chromatin and regulates gene expression. The Saccharomyces cerevisiae inner ring nucleoporin Nup170 has been implicated in chromatin organization and the maintenance of gene silencing in subtelomeric regions. To gain insight into how Nup170 regulates this process, we used protein-protein interactions, genetic interactions, and transcriptome correlation analyses to identify the Ctf18-RFC complex, an alternative proliferating cell nuclear antigen (PCNA) loader, as a facilitator of the gene regulatory functions of Nup170. The Ctf18-RFC complex is recruited to a subpopulation of NPCs that lack the nuclear basket proteins Mlp1 and Mlp2. In the absence of Nup170, PCNA levels on DNA are reduced, resulting in the loss of silencing of subtelomeric genes. Increasing PCNA levels on DNA by removing Elg1, which is required for PCNA unloading, rescues subtelomeric silencing defects in nup170Δ. The NPC, therefore, mediates subtelomeric gene silencing by regulating PCNA levels on DNA.
Topics: Carrier Proteins; Chromatin; Gene Silencing; Nuclear Pore; Proliferating Cell Nuclear Antigen; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Telomere; DNA, Fungal
PubMed: 37358474
DOI: 10.1083/jcb.202207060 -
Biomolecules Apr 2022Human S100B is a small, multifunctional protein. Its activity, inside and outside cells, contributes to the biology of the brain, muscle, skin, and adipocyte tissues....
Human S100B is a small, multifunctional protein. Its activity, inside and outside cells, contributes to the biology of the brain, muscle, skin, and adipocyte tissues. Overexpression of S100B occurs in Down Syndrome, Alzheimer's disease, Creutzfeldt-Jakob disease, schizophrenia, multiple sclerosis, brain tumors, epilepsy, melanoma, myocardial infarction, muscle disorders, and sarcopenia. Modulating the activities of S100B, related to human diseases, without disturbing its physiological functions, is vital for drug and therapy design. This work focuses on the extracellular activity of S100B and one of its receptors, the Receptor for Advanced Glycation End products (RAGE). The functional outcome of extracellular S100B, partially, depends on the activation of intracellular signaling pathways. Here, we used Biotin Switch Technique enrichment and mass-spectrometry-based proteomics to show that the appearance of the S100B protein in the extracellular milieu of the mammalian Chinese Hamster Ovary (CHO) cells, and expression of the membrane-bound RAGE receptor, lead to changes in the intracellular S-nitrosylation of, at least, more than a hundred proteins. Treatment of the wild-type CHO cells with nanomolar or micromolar concentrations of extracellular S100B modulates the sets of S-nitrosylation targets inside cells. The cellular S-nitrosome is tuned differently, depending on the presence or absence of stable RAGE receptor expression. The presented results are a proof-of-concept study, suggesting that S-nitrosylation, like other post-translational modifications, should be considered in future research, and in developing tailored therapies for S100B and RAGE receptor-related diseases.
Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Humans; Protein S; Receptor for Advanced Glycation End Products; Receptors, Immunologic; S100 Calcium Binding Protein beta Subunit
PubMed: 35625541
DOI: 10.3390/biom12050613