Nucleocytoplasmic O-GlcNAc transferase (OGT) attaches a single GlcNAc to hydroxyl groups of serine and threonine residues. Although the cellular localisation of OGT is important to regulate a variety of cellular processes, the molecular mechanisms regulating the nuclear localisation of OGT is unclear. Here, we characterised three amino acids (DFP; residues 451–453) as the nuclear localisation signal of OGT and demonstrated that this motif mediated the nuclear import of non-diffusible β-galactosidase. OGT bound the importin α5 protein, and this association was abolished when the DFP motif of OGT was mutated or deleted. We also revealed that O-GlcNAcylation of Ser389, which resides in the tetratricopeptide repeats, plays an important role in the nuclear localisation of OGT. Our findings may explain how OGT, which possesses a NLS, exists in the nucleus and cytosol simultaneously.

See Hart and Huang (doi: ) for a scientific commentary on this article. Lee et al. show that O-GlcNAcylation, an evolutionarily conserved post-translational modification, is critical for the physiological functioning and survival of dopaminergic neurons. Upregulating O-GlcNAcylation mitigates neurodegeneration, synaptic impairments and motor deficits in a mouse model of Parkinson’s disease.

Background Since the declaration of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 has affected the responses of emergency medical service (EMS) systems to cases of out-of-hospital cardiac arrest (OHCA). The purpose of this study was to identify the impact of the COVID-19 pandemic on EMS responses to and outcomes of adult OHCA in an area of South Korea. Methods This was a retrospective observational study of adult OHCA patients attended by EMS providers comparing the EMS responses to and outcomes of adult OHCA during the COVID-19 pandemic to those during the pre-COVID-19 period. Propensity score matching was used to compare the survival rates, and logistic regression analysis was used to assess the impact of the COVID-19 pandemic on the survival of OHCA patients. Results A total of 891 patients in the pre-COVID-19 group and 1,063 patients in the COVID-19 group were included in the final analysis. During the COVID-19 period, the EMS call time was shifted to a later time period (16:00–24:00, P < 0.001), and the presence of an initial shockable rhythm was increased (pre-COVID-19 vs. COVID-19, 7.97% vs. 11.95%, P = 0.004). The number of tracheal intubations decreased (5.27% vs. 1.22%, P < 0.001), and the use of mechanical chest compression devices (30.53% vs. 44.59%, P < 0.001) and EMS response time (median [quartile 1-quartile 3], 7 [5–10] vs. 8 [6–11], P < 0.001) increased. After propensity score matching, the survival at admission rate (22.52% vs. 18.24%, P = 0.025), survival to discharge rate (7.77% vs. 5.52%, P = 0.056), and favorable neurological outcome (5.97% vs. 3.49%, P < 0.001) decreased. In the propensity score matching analysis of the impact of COVID-19, odds ratios of 0.768 (95% confidence interval [CI], 0.592–0.995) for survival at admission and 0.693 (95% CI, 0.446–1.077) for survival to discharge were found. Conclusion During the COVID-19 period, there were significant changes in the EMS responses to OHCA. These changes are considered to be partly due to social distancing measures. As a result, the proportion of patients with an initial shockable rhythm in the COVID-19 period was greater than that in the pre-COVID-19 period, but the final survival rate and favorable neurological outcome were lower.

O-GlcNAcylation is highly involved in cellular stress responses including the endoplasmic reticulum (ER) stress response. For example, glucosamine-induced flux through the hexosamine biosynthetic pathway can promote ER stress and ER stress inducers can change the total cellular level of O-GlcNAcylation. However, it is largely unknown which component(s) of the unfolded protein response (UPR) is directly regulated by O-GlcNAcylation. In this study, eukaryotic translation initiation factor 2α (eIF2α), a major branch of the UPR, was O-GlcNAcylated at Ser 219, Thr 239, and Thr 241. Upon ER stress, eIF2α is phosphorylated at Ser 51 by phosphorylated PKR-like ER kinase and this inhibits global translation initiation, except for that of specific mRNAs, including activating transcription factor 4, that induce stress-responsive genes such as C/EBP homologous protein (CHOP). Hyper-O-GlcNAcylation induced by O-GlcNAcase inhibitor (thiamet-G) treatment or O-GlcNAc transferase (OGT) overexpression hindered phosphorylation of eIF2α at Ser 51. The level of O-GlcNAcylation of eIF2α was changed by dithiothreitol treatment dependent on its phosphorylation at Ser 51. Point mutation of the O-GlcNAcylation sites of eIF2α increased its phosphorylation at Ser 51 and CHOP expression and resulted in increased apoptosis upon ER stress. These results suggest that O-GlcNAcylation of eIF2α affects its phosphorylation at Ser 51 and influences CHOP-mediated cell death. This O-GlcNAcylation of eIF2α was reproduced in thiamet-G-injected mouse liver. In conclusion, proper regulation of O-GlcNAcylation and phosphorylation of eIF2α is important to maintain cellular homeostasis upon ER stress.

Adefovir dipivoxil (ADV) is a nucleotide used as long-term therapy of chronic hepatitis B. Many published reports have shown that long-term high-dose therapy with adefovir can be associated with proximal renal tubular dysfunction resulting in significant hypophosphatemia, renal insufficiency and osteomalacia. We have encountered two patients who developed evidence of hypophosphatemic osteomalacia while on long-term low-dose adefovir therapy for chronic hepatitis B. We report on its clinical features and its potential resolution with cessation of the drug and supplementation with phosphate. We also reviewed the other published cases associated with hypophosphatemic osteomalacia after low-dose adefovir therapy. The symptoms and the hypophosphatemia improved after cessation of the drug and supplementation with phosphate in most cases. Patients taking adefovir long-term should receive regular investigation of the phosphate level and renal function.