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PubMed2024

Dissecting OGT's TPR domain to identify determinants of cellular function.

O-GlcNAc transferase (OGT) is an essential mammalian enzyme that glycosylates myriad intracellular proteins and cleaves the transcriptional coregulator Host Cell Factor 1 to regulate cell cycle processes. Via these catalytic activities as well as noncatalytic protein-protein interactions, OGT maintains cell homeostasis. OGT's tetratricopeptide repeat (TPR) domain is important in substrate recognition, but there is little information on how changing the TPR domain impacts its cellular functions. Here, we investigate how altering OGT's TPR domain impacts cell growth after the endogenous enzyme is deleted. We find that disrupting the TPR residues required for OGT dimerization leads to faster cell growth, whereas truncating the TPR domain slows cell growth. We also find that OGT requires eight of its 13 TPRs to sustain cell viability. OGT-8, like the nonviable shorter OGT variants, is mislocalized and has reduced Ser/Thr glycosylation activity; moreover, its interactions with most of wild-type OGT's binding partners are broadly attenuated. Therefore, although OGT's five N-terminal TPRs are not essential for cell viability, they are required for proper subcellular localization and for mediating many of OGT's protein-protein interactions. Because the viable OGT truncation variant we have identified preserves OGT's essential functions, it may facilitate their identification.

N-Acetylglucosaminyltransferases↗

PubMed2026

Binding analysis of the response regulator NarL protein to the promoter of the O6-methylguanine-DNA methyltransferase (ogt) gene in Salmonella Typhimurium.

BACKGROUND: Salmonella Typhimurium (STM) is a gram-negative bacterium that causes severe gastrointestinal disorders in both animals and humans. The regulation of DNA repair genes is critical for maintaining genomic stability of the bacteria. O6-methylguanine DNA methyltransferase (Ogt), plays a vital role in repairing alkylated DNA in STM; however, the transcriptional regulation of ogt gene remains poorly characterized. Furthermore, NarL is a transcriptional regulator, involved in the pathogenesis of STM under anaerobic condition. Therefore, this study investigated the interaction between NarL protein and the promoter region of the ogt gene. METHODS: In this study, narl gene was cloned in pET32a vector and NarL protein was expressed in Escherichia coli BL21 (DE3). Subsequently, the ogt gene promoter (pogt) was selected, amplified, cloned and its activity was evaluated. Electrophoretic mobility shift assay (EMSA), isothermal titration calorimetry (ITC), molecular docking were employed to elucidate the interaction between NarL protein and ogt promoter. Furthermore, the regulatory role of NarL in ogt gene expression was validated in vivo using RT-qPCR and β-galactosidase assay. RESULTS: This study resulted that NarL protein interacts specifically with the ogt promoter, as confirmed by EMSA and ITC, with ΔG of - 9.42 kcal mol⁻¹. Furthermore, RT-qPCR and β-galactosidase assays demonstrated that deletion of narl significantly (P ≤ 0.01) decreased ogt transcript levels and promoter activity than wild Salmonella Typhimurium, whereas exogenous supplementation of recombinant NarL protein restored the expression. These findings suggest that NarL plays a potential regulatory role in ogt gene expression in response to environmental signals. CONCLUSION: These findings highlight an interaction between NarL protein and the promoter region of ogt gene in Salmonella Typhimurium, linking nitrogen metabolism with the DNA repair pathway in STM, which may contribute to the bacterial survival under nitrosative stress.

Salmonella typhimurium↗

PubMed2026

Regulation of TET function by PROSER1 in development and hematologic malignancies.

Ten eleven translocation (TET) proteins are central regulators of DNA methylation homeostasis and play essential roles in development and disease, including hematopoietic malignancies. Among the three TET family members, mutations in TET2 are frequently observed in hematologic disorders. TET enzymes catalyze the iterative oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, enabling DNA demethylation. Beyond catalysis, TET proteins also perform important non-enzymatic functions mediated through interactions with diverse protein partners, highlighting the importance of defining their regulatory interactome. Previous studies identified several TET-associated factors, including O-Linked N-acetylglucosamine transferase (OGT), members of the Drosophila behavior/human splicing (DBHS) protein family, and proline and serine-rich protein 1 (PROSER1). However, these interactions were largely considered independently. Recent findings now demonstrate that TET proteins, OGT, PROSER1, and DBHS proteins assemble into a higher-order regulatory unit termed the TOPD (TET-OGT-PROSER1-DBHS) complex. In this review, we discuss how TOPD provides a conceptual framework for understanding multicomponent regulation of TET function, spatial control of DNA demethylation, and maintenance of epigenetic homeostasis, with implications for developmental syndromes and hematopoiesis.

Humans↗

PubMed1978

[Effect of long-term treatment with neuroleptics or lithium salts on carbohydrate metabolism].

Long-term treatments with neuroleptic drugs or lithium salts are well established and, with regard to side-effects, possess a common denominator: both treatments may increase the body weight, and may influence in different, even contrary ways the carbohydrate metabolism. In this study the oral glucose tolerance test (oGTT) including the determination of immunologically measurable insulin (IMI) has been performed in 49 lithium-treated out-patients, and in 125 inpatients under neuroleptic long-term treatment. The test was repeated within six months in the lithium-group. 3 different evaluation criteria were used. Among the patients with neuroleptic treatment there were 25 to 36% with a pathological glucose tolerance curve; the expected frequency would have been approx. 8%. 55% of the patients had overweight, which positively correlated to the occurrence of pathological glucose tolerance. 24.5 to 30.6% of cases with pathological oGT were found in the lithium-group. 69% of the patients had overweight; age and overweight positively correlated with pathological oGT. According to the very conservative criterion of the European Study Group (EDESG), the still increased frequency of pathological oGT curves in the second investigation, compared to epidemiological data, just failed statistical significance. The results suggest that also under long-term lithium treatment an increased lability of carbohydrate metabolism, be it due to the drug or the manic-depressive disease, must be discussed as a potential risk for the patient.

Adult↗

PubMed2025

The Role of Polo-Like Kinase 1 (PLK1) O-GlcNAcylation in Mitosis.

Polo-like kinase 1 (PLK1) is a crucial mitotic kinase that is implicated in various aspects of cell cycle. Many post-translational modifications have been identified on PLK1 to regulate its activation, stability, and localization. PLK1 has been shown previously to colocalize with the O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT), and OGT regulates PLK1 stability. In our recent work, we show that PLK1 is O-GlcNAcylated by click chemistry. Using stepped collisional energy/higher energy collision dissociation mass spectrometry, we mapped the PLK1 O-GlcNAc site to be T291. We further utilized fluorescent activated cell sorting and time-lapse microscopy to assess the mitotic defects of PLK1 O-GlcNAc mutants. In vivo studies in mouse xenograft demonstrated that it promoted uterine cancer tumorigenesis. In this chapter, we delineate the methodologies we used in studying PLK1 O-GlcNAcylation, including click chemistry, stepped collisional energy/higher energy collision dissociation mass spectrometry, fluorescent activated cell sorting, time-lapse microscopy, and mouse xenograft assays.

Polo-Like Kinase 1↗

PubMed2023

H4S47 O-GlcNAcylation regulates the activation of mammalian replication origins.

The transmission and maintenance of genetic information in eukaryotic cells relies on the faithful duplication of the entire genome. In each round of division, excessive replication origins are licensed, with only a fraction activated to give rise to bi-directional replication forks in the context of chromatin. However, it remains elusive how eukaryotic replication origins are selectively activated. Here we demonstrate that O-GlcNAc transferase (OGT) enhances replication initiation by catalyzing H4S47 O-GlcNAcylation. Mutation of H4S47 impairs DBF4-dependent protein kinase (DDK) recruitment on chromatin, causing reduced phosphorylation of the replicative helicase mini-chromosome maintenance (MCM) complex and compromised DNA unwinding. Our short nascent-strand sequencing results further confirm the importance of H4S47 O-GlcNAcylation in origin activation. We propose that H4S47 O-GlcNAcylation directs origin activation through facilitating MCM phosphorylation, and this may shed light on the control of replication efficiency by chromatin environment.

Animals↗

PubMed2026

Rare variant analysis of whole genome sequenced juvenile idiopathic arthritis multiplex pedigrees identifies rare variants in NOD2 and ACVR1.

Juvenile idiopathic arthritis is a complex rheumatic disease that is influenced by environmental and genetic factors. Linkage and genome-wide association studies have identified genes that contribute to the risk of developing juvenile idiopathic arthritis but are limited in their ability to identify disease-risk variants of large effect. Penetrant, heritable risk variants can be detected in high-risk families, but such cases are uncommon due to the low prevalence of juvenile idiopathic arthritis. This study utilizes whole-genome sequencing of 23 multiplex families, the largest such cohort to date, to discover variants and genes relevant to JIA pathogenesis. Pathogenic variants in NOD2 associated with Blau syndrome, an ultra-rare Mendelian inflammatory disorder, are the most recurrent variants in the cohort, consistent with previous reports that milder presentations of Blau syndrome are oftentimes misdiagnosed as juvenile idiopathic arthritis. For the first time, however, rare variants in ACVR1 and SMAD6, integral components of the Bone Morphogenic Protein pathway, are found to be associated with juvenile idiopathic arthritis. Identified ACVR1 variants map to critical protein domains. AlphaFold modeling predicts that the ACVR1 interaction with its inhibitor OGT is disrupted by these variants, indicating that the patient-mutated protein has a gain-of-function phenotype. Drosophila melanogaster expressing either a wild-type or patient-mutated version of ACVR1 exhibit embryonic lethality, with the mutant exhibiting 1.4-fold greater lethality than wild-type. The combination of family-based cohorts for gene discovery, AI-based computational tools, and animal model studies for tests of variant function underscores shared disease pathogenesis between JIA and monogenic disorders of immunity and connective tissue.

Arthritis, Juvenile↗

PubMed1978

Effects of in vivo and in vitro dialysis on plasma transaminase activity.

The effects of dialysis on plasma glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) were investigated. GOT was measured using Autoanalyzer (SMA) and kinetic (Karmen) methods. Hemodialysis of uremic subjects was associated with a significant increase of GOT (SMA) and GPT (SMA). In contrast, hemodialysis had no effect on GOT (Karmen). However, the SMA method is influenced by substances affecting the blank value. Therefore, the results suggest that the increase in transaminase activities measured by the SMA method are not due to true increases in enzyme activities. Plasma from dialysis patients, obtained prior to hemodialysis, was also dialyzed in vitro. In vitro dialysis of uremic plasma significantly increased GOT (SMA), GOT (Karmen) and GPT vitro dialysis of uremic plasma significantly increased GOT (SMA), OGT (Karmen) and GPT (SMA). The results suggest that an inhibitor of transaminase activity may accumulate in renal failure. In vitro dialysis may remove this inhibitor and thus increase true transaminase activity.

Alanine Transaminase↗

PubMed1977

Development and use of single "polytropic" diagnostic tubes for the approximate taxonomic grouping of bacteria isolated from foods, water and medicinal preparations.

Single tubes, containing in all instances a bottom layer of a solid medium for detecting mode of attack on glucose, lactose, mannitol or starch and top layers of solid, semi-solid or liquid media allowing assessment of motility, formation of catalase, oxidase, coagulase, indole, hydrogen sulphide, acetyl methyl carbinol or pigments, as required ("polytropic" diagnostic tubes) were developed for the approximate taxonomic grouping of bacteria commonly encountered in foods, water and medicinal preparations. They are designated as: Gram negative diagnostic tubes (GNT), tubes allowing identification of E. coli, following the principle set out by MCKENZIE, TAYLOR and GILBERT (MTGT), diagnostic tubes for Vibrio parahaemolyticus (VPT), open tubes to assess oxidative attack on glucose (OGT), Gram positive diagnostic tubes (GPT), and mannitol plasma tubes (MPT) for the identification of Staph. aureus. In addition a CP tube for the identification of Cl. perfringens is described, the basis of which is the production of H2S from sulphite in the presence of cycloserine, absence of mitality and failure to produce indole at 46 degrees C. All tubes contain intermediate layers to avoid interactions between changes occurring in top and bottom layers. Upon examination of about 600 pure cultures from collections or freshly isolated from foods etc. such tubes have given results which were in agreement with those of classical testing; in a few instances (testing for indole formation) even better results were obtained. The use of such polytropic tubes in identification routes saving much time and effort is outlines.

Bacteria↗