bims-meglyc 2025-08-10 papers

Issue of 2025–08–10
four papers selected by
Silvia Radenkovic, UMC Utrecht

Front Endocrinol (Lausanne). 2025 ;16 1594118

Phosphomannomutase 2-congenital disorder of glycosylation: exploring the role of N-glycosylation on the endocrine axes.

Giulia Del Medico, Lorenzo Ferri, Elena Procopio, Giosuè Annibalini, Elena Barbieri, Rita Barone, Renzo Guerrini, Amelia Morrone, Stefano Stagi.

Congenital disorders of glycosylation (CDG) are a heterogeneous group of inborn errors of metabolism caused by impaired protein glycosylation. Among these, PMM2-CDG, caused by defective phosphomannomutase 2 activity and affecting protein N-glycosylation, is the most prevalent. As glycoproteins are involved in almost every physiological process, the clinical manifestations in PMM2-CDG are diverse and multisystemic. In the endocrine system, glycoproteins are present in every axis, acting as hormones, prohormones, receptors, enzymes, and transport proteins. Hypoglycosylation can alter hormonal function on multiple levels. As a result, endocrinopathies are frequently part of the clinical spectrum of PMM2-CDG, particularly hypergonadotrophic hypogonadism and pubertal abnormalities in female patients. Symptoms of endocrine involvement, especially hyperinsulinemic hypoglycemia and failure to thrive during infancy, can be the presenting sign of the disease. The clinical spectrum of PMM2-CDG endocrinopathy is variable; for example, thyroid involvement can range from isolated transitory hyperthyrotropinemia to clinical hypothyroidism. Some endocrine abnormalities, such as adrenal insufficiency, are uncommon and probably underdiagnosed in PMM2-CDG. The new insights into the role of N-glycosylation on the endocrine system over the past twenty years have deepened our understanding of this complex disorder and should enable us to improve and personalize the clinical management of these patients.

Keywords: N-glycosylation; congenital disorder of glycosylation; endocrine dysfunction; hypergonadotropic hypogonadism; hypoglycosylation

DOI: https://doi.org/10.3389/fendo.2025.1594118

Sci Rep. 2025 Aug 03. 15(1): 28328

HCF-1 as a key modulator of OGT function and O-GlcNAcylation in the liver.

Vaibhav Kapuria, Ayushma, Winship Herr, Shilpi Minocha.

Host cell factor-1 (HCF-1) is a transcriptional coregulator essential for maintaining liver function and cellular metabolism. O-linked N-acetylglucosamine transferase (OGT) is a key nutrient-sensing enzyme that catalyzes protein O-GlcNAcylation, a critical post-translational modification regulating metabolic pathways. This study investigates the role of hepatocyte-specific depletion of HCF-1 in regulating OGT stability, activity, and cellular localization in hepatocytes. Using a transgenic mouse model with hepatocyte-specific HCF-1 deletion, we assessed the impact of HCF-1 loss on OGT expression and O-GlcNAcylation activity. OGT protein levels, mRNA expression, and cellular localization were evaluated using molecular and histological techniques. Comparisons were made with control mice and hepatocytes under nutrient-starved conditions. Hepatocyte-specific HCF-1 deletion led to progressive loss of HCF-1 protein and a concomitant decrease in OGT levels and global O-GlcNAcylation. Loss of HCF-1 did not alter OGT mRNA levels, suggesting post-translational regulation. Immunofluorescence revealed reduced nuclear OGT and O-GlcNAcylation, mimicking changes observed under fasting conditions. Isolated HCF-1-deficient hepatocytes showed impaired adhesion, further underscoring HCF-1's role in hepatocyte function. Notably, in heterozygous Hcfc1hepKO/ + females, HCF-1-negative hepatocytes displayed cytoplasmic O-GlcNAcylation, while HCF-1-positive cells maintained nuclear localization. HCF-1 is crucial for regulating OGT stability, activity, and nuclear localization in hepatocytes. These findings establish a mechanistic link between HCF-1 and OGT, highlighting their coordinated role in hepatic nutrient sensing and metabolic regulation.

Keywords: O-GlcNAcylation; O‐linked N‐acetylglucosamine (O‐GlcNAc) transferase (OGT); Hepatocytes; Host cell factor-1; Liver; Nutrient sensing.

DOI: https://doi.org/10.1038/s41598-025-11813-1

PLoS Genet. 2025 Aug 07. 21(8): e1011823

Natural SEL1L variants rescue a model of NGLY1 deficiency and modify ERAD function and proteasome sensitivity.

Travis K Tu'ifua, Clement Y Chow.

N-glycanase 1 (NGLY1) deficiency is an ultra-rare disease caused by autosomal recessive loss-of-function mutations in the NGLY1 gene. NGLY1 removes N-linked glycans from glycoproteins in the cytoplasm and is thought to help clear misfolded proteins from the endoplasmic reticulum (ER) through the ER associated degradation (ERAD) pathway. Despite this, the physiological significance of NGLY1 in ERAD is not understood. The best characterized substrate of NGLY1 is NRF1, a transcription factor that upregulates proteasome expression and the proteasome bounce-back response. We previously performed a genetic modifier screen using a Drosophila model of NGLY1 deficiency and identified potential modifiers that alter the lethality of the model. We identified two protein-coding variants in Hrd3/SEL1L: S780P and Δ806-809. Both variants are localized to the SEL1L cytoplasmic tail, an uncharacterized domain. SEL1L is a component of the ERAD complex that retrotranslocates misfolded proteins from the ER to the cytoplasm for degradation. We used CRISPR to generate fly lines carrying these SEL1L variants in a common genetic background and tested them with our model of NGLY1 deficiency. Validating our previous screen, the SEL1LS780P and SEL1LΔ806-809 variants increased the survival of the NGLY1 deficiency model, compared to the SEL1LS780 variant. To determine how these SEL1L variants were modifying lethality in NGLY1 deficiency, we interrogated the ERAD and NRF1 signaling pathways. We found that the SEL1LS780P and SEL1LΔ806-809 variants improve resistance to ER stress, with enhanced ERAD function as a likely contributing mechanism. This effect depends on NGLY1 activity, further implicating NGLY1 in general ERAD function. We also found that, in heterozygous NGLY1 null flies, these variants protect against some defects like increased lethality caused by proteasome inhibition. These results provide new insights into the role of SEL1L in the disease pathogenesis of NGLY1 deficiency. SEL1L is a strong candidate modifier gene in patients, where variability in presentation is common.

DOI: https://doi.org/10.1371/journal.pgen.1011823

Arterioscler Thromb Vasc Biol. 2025 Aug 07.

Plasma N-Glycan Signatures Are Associated With a First Event of Venous Thromboembolism.

Ruifang Li-Gao, Marco R Bladergroen, Frits R Rosendaal, Manfred Wuhrer, Astrid van Hylckama Vlieg.

BACKGROUND: Coagulation factors play important roles in the pathophysiology of venous thromboembolism (VTE), and most of them are glycoproteins, that is, proteins containing glycans attached. Although the connection between glycosylation and coagulation factors seems obvious, the association between glycosylation and VTE risk remains unexplored. We aimed to elucidate the association between N-glycans in plasma and VTE risk in the MEGA study (Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis), a case-control study aiming to identify risk factors for VTE.
METHODS: The total plasma N-glycomes of 491 VTE cases with a first idiopathic VTE and 472 controls were analyzed using a robust mass spectrometry platform. In total, 91 N-glycans were measured. The association between each N-glycan and the risk of a first VTE was analyzed with logistic regression models, adjusted for potential confounders. In addition, we also examined the associations between VTE-associated N-glycans as well as glycosylation features and VTE-associated coagulation factors with linear regression models.
RESULTS: In the analysis, 466 idiopathic VTE cases and 454 controls were included. We found that fucosylation of complex-type glycans and the presence of more antennae in glycan structures were associated with an increased risk of VTE. Conversely, monoantennary and diantennary complex-type glycans, as well as oligomannose-type glycans, were associated with a reduced risk of VTE. The associations between glycan features and VTE risk were partially supported by their relationships with procoagulant factors.
CONCLUSIONS: We demonstrated the relevance of plasma N-glycan signatures in the risk of a first VTE. Plasma N-glycome holds a strong potential for VTE risk stratification.

Keywords: blood coagulation factors; glycoproteins; glycosylation; risk factors; venous thromboembolism

DOI: https://doi.org/10.1161/ATVBAHA.125.323205