bims-meglyc 2026-05-24 papers

Issue of 2026–05–24
three papers selected by
Silvia Radenkovic, UMC Utrecht

J Clin Endocrinol Metab. 2026 May 21. pii: dgag212. [Epub ahead of print]

Dysregulation of glycogen metabolism in cardiomyopathy caused by glycogenin-1 (GYG1) missense variants.

Kittichate Visuttijai, Carola Hedberg-Oldfors, Oscar Braun, Elisabet Englund, Emma Glamuzina, Clinton Turner, Kristina Vukusic, Joakim Sandstedt, Göran Dellgren, Kristjan Karason, Anders Oldfors.

CONTEXT: Glycogen storage diseases are inherited disorders of glycogen metabolism and are commonly associated with hypoglycaemia, hepatic dysfunction, or skeletal and cardiac myopathy, depending on the affected enzyme. Glycogen storage disease type 15 (GSD15) is caused by pathogenic variants in GYG1, which encodes glycogenin-1, the auto-glucosylating primer required for glycogen synthesis. GSD15 is characterized by cardiomyopathy and storage of abnormal glycogen and polyglucosan in cardiomyocytes.
OBJECTIVE: To understand the pathobiology of GSD15, we investigated the storage material in heart explants from two previously reported patients and describe a new case of GSD15.
METHODS: The characteristic storage material was investigated using laser capture microdissection followed by quantitative mass spectrometry (MS) and immunohistochemistry comparing differentially abundant proteins in the storage material with normal-appearing cytoplasmic regions from the same patient. Global protein dysregulation in GSD15 was assessed by quantitative MS of whole-myocardial tissue samples from patients and normal controls.
RESULTS: The storage material was enriched in proteins involved in glycogen metabolism, including glycogen synthase, UDP-glucose pyrophosphorylase 2, glycogenin-1, glycogen phosphorylase, and glycogen debranching enzyme. Sequestosome 1 (p62) and desmin were also enriched, without evidence of increased autophagocytosis. Whole-tissue analyses revealed upregulation of cardiomyopathy-associated biomarkers and downregulation of mitochondrial proteins, suggesting impaired energy metabolism contributing. to congestive heart failure.
CONCLUSIONS: In GSD15, storage of abnormal glycogen in cardiomyocytes is associated with enrichment of specific proteins involved in glycogen metabolism, contributing to dysregulation of glycogen turnover. This dysregulation results in polyglucosan accumulation, disruption of sarcomeric and mitochondrial architecture, and progressive fibrosis. No disease-modifying therapy currently exists for GSD15; future strategies based on substrate reduction, enhancement of autophagy, or gene therapy require further investigation.

Keywords: GYG1 ; Glycogen storage disease XV; PGBM2; Polyglucosan body myopathy 2; cardiomyopathy; proteomic profiling

DOI: https://doi.org/10.1210/clinem/dgag212

Glycobiology. 2026 May 18. pii: cwag038. [Epub ahead of print]

Cellular homeostasis of N-acetylneuraminic acid and non-canonical sialic acids is mediated by human N-acetylneuraminate lyase.

Sjanie Huang, Iris Harmsen, Moritz Rahm, Takfarinas Kentache, Clara D M van Karnebeek, Afitz Da Silva, Alexey V Pshezhetsky, Emile Van Schaftingen, Alejandro Garanto, Dirk J Lefeber.

Sialic acids are important for cellular communication, with N-acetylneuraminic acid (Neu5Ac) being the canonical form of sialic acid in humans. Presence of non-canonical sialic acids, derived from dietary intake or as metabolic side product, has been linked to immune disorders and cancer. As homeostasis of different sialic acids remains poorly understood in humans, we studied the role of N-acetylneuraminate lyase (NPL) in their catabolism. In vitro expression of NPL in different biological systems revealed broad substrate specificity towards sialic acids and related 2-keto-3-deoxy metabolites. In agreement with the broad substrate specificity, NPL-deficient red blood cells accumulated Neu5Ac and 3-deoxy-d-glycero-d-galacto-nonulosonic acid (KDN). Interestingly, endogenous levels of non-canonical sialic acids, including N-glycolylneuraminic acid (Neu5Gc) and KDN, were depleted in HEK293T cells upon NPL overexpression, while Neu5Ac and CMP-Neu5Ac levels remained stable. This was further confirmed by supplementation with different sialic acids. Detailed analysis of sugar phosphate intermediates of the hexosamine and sialic acid biosynthesis pathways showed strongly elevated ManNAc-6P (N-acetyl-d-mannosamine 6-phosphate) and Neu5Ac-9P, indicating efficient recycling of ManNAc to increase de novo Neu5Ac biosynthesis. However, this recycling was not efficient for Neu5Gc and KDN. While GlcNAc-6P (N-acetyl-d-glucosamine 6-phosphate) levels were slightly elevated, no evidence was found for further metabolism towards GlcN-6P (glucosamine 6-phosphate) and energy production via glycolysis as shown for bacterial neuraminate lyases. In conclusion, human NPL catabolizes a broad range of sialic acids. However, depending on the cellular context, NPL contributes to a net cellular reduction in non-canonical sialic acids, such as KDN, due to a lack of efficient recycling.

Keywords: N-acetylneuraminate lyase; enzyme function; metabolism; neuraminic acid; sialic acid

DOI: https://doi.org/10.1093/glycob/cwag038

Cell Death Differ. 2026 May 21.

ALG1-mediated PDL1 glycosylation drives macrophage m2 polarization to promote bladder cancer progression.

J G Zhao, Z Y Chen, H Q Pan, Y Jin, R Y Zhang, Y C Zheng, W Y Cai.

Asparagine-linked glycosylation protein 1 homolog (ALG1), a β-1,4-mannosyltransferase, catalyzes the initial committed step of the N-glycosylation pathway. While its role in congenital glycosylation disorders is well established, the contribution of ALG1 to bladder cancer (BC) progression, particularly its impact on the tumor immune microenvironment, remains poorly understood. In this multi-omics study, we delineated the pathological significance and molecular mechanisms of ALG1 in BC. We demonstrated that ALG1 directly interacted with programmed death-ligand 1 (PDL1) and catalyzed its glycosylation, as confirmed by site-directed mutagenesis and glycosidase inhibitor treatments. This modification stabilized PDL1 by shielding it from ubiquitin-mediated proteasomal degradation, thereby enhancing its protein stability and cell surface expression. Consequently, ALG1-driven PDL1 glycosylation amplified immunosuppressive signaling via sustained PD1/PDL1 engagement, promoting tumor-associated macrophage M2 (TAM-M2) polarization and facilitating tumor immune evasion. These collective effects reshaped the tumor microenvironment toward an immunosuppressive state, enabling immune escape. Both in vitro and in vivo experiments demonstrated that genetic inhibition of ALG1 effectively reversed PDL1-mediated immunosuppression and restored sensitivity to anti-PD1 therapy. In summary, our study identified ALG1 as a critical post-translational regulator of PDL1 stability and immunosuppression in BC, and targeting ALG1-mediated glycosylation represented a promising therapeutic strategy to enhance immunotherapy efficacy and overcome immune evasion in BC patients.

DOI: https://doi.org/10.1038/s41418-026-01764-z