bims-meglyc 2026-06-14 papers

Issue of 2026–06–14
four papers selected by
Silvia Radenkovic, UMC Utrecht

Int J Mol Sci. 2026 Jun 05. pii: 5119. [Epub ahead of print]27(11):

Distinct O-Linked Glycosylation Systems in Signaling and Immune Regulation.

Shuguang Wang, Shibo Xiao, Yuman Huang, Xianwang Wang.

O-linked glycosylation comprises distinct regulatory systems, including secretory-pathway mucin-type O-GalNAc glycosylation and intracellular O-GlcNAcylation. These modifications both target serine/threonine residues but differ in glycan structure, cellular compartment, enzymatic machinery, and biological function. This narrative review was based on targeted searches of PubMed, Web of Science, and related literature using keywords related to O-glycosylation, O-GalNAc glycosylation, O-GlcNAcylation, immune regulation, cell signaling, glycoproteomics, and congenital disorders of glycosylation (CDG). We summarize evidence that mucin-type O-glycosylation regulates receptor behavior, cell adhesion, immune checkpoints, immunoglobulin function, antigen recognition, and pathogen-host interactions, whereas O-GlcNAcylation mainly modulates intracellular signaling, transcriptional control, stress responses, post-translational modification crosstalk, and innate immune pathways. We also discuss how glycosylation defects, including CDG and selected O-linked glycosylation disorders, connect genetic variation with disease phenotypes. Recent advances in site-specific glycoproteomics, O-glycoprotease-assisted workflows, LC-MS/MS-based glycopeptide analysis, and spatial or temporal profiling have improved mechanistic interpretation but still face limitations in site localization, structural resolution, and functional validation. Overall, the evidence supports the hypothesis that distinct O-linked glycosylation systems act through different molecular mechanisms but converge on signaling regulation, immune homeostasis, and disease susceptibility.

Keywords: O-glycosylation; cell signaling; disease pathogenesis; glycoproteomics; immune regulation

DOI: https://doi.org/10.3390/ijms27115119

J Proteomics. 2026 Jun 08. pii: S1874-3919(26)00098-9. [Epub ahead of print]330 105695

ALG13 deficiency impairs cortical development via suppression of the PI3K/AKT/mTOR pathway.

Baorui Guo, Xiuhua Li, Zhijie Yang, Yangyang Sun, Jiayu Liu, Peng Gao, Zhuoqi Li, Lei Liang, Gang Cheng, Wenying Lv, Zhifa Zhang, Shengqiang Xie, Hanbo Zhang, Yuxin Wang, Ao Xu, Shichao Su, Tao Sun, Jianning Zhang.

ALG13 mutations cause congenital disorders of glycosylation and neurodevelopmental deficits, but how asparagine-linked glycosylation 13 (ALG13) deficiency impairs brain development remains unclear. This study aimed to elucidate the underlying mechanisms in Alg13 knockout (ALG13KO) mice. We first confirmed neurodevelopmental delays and abnormal cortical neuron distribution in ALG13KO mice. Quantitative proteomic analysis of the postnatal day 7 cerebral cortex revealed widespread protein abundance changes. Subsequent bioinformatic and protein-protein interaction net-work analyses pinpointed the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway. Pathway as a central hub. Parallel reaction monitoring validated the downregulation of key upstream regulators Laminin γ-1 (LAMC1), Focal Adhesion Kinase (FAK), and Integrin α6 (ITGA6). Western blot confirmed the inhibition of PI3K/AKT/mTOR phosphorylation. Our findings demonstrate that ALG13 deficiency disrupts cortical development, likely via suppression of the PI3K/AKT/mTOR pathway through the LAMC1-ITGA6-FAK axis. This study reveals a critical, early-developmental suppression of mTOR signaling, contrasting with its reported hyperactivation in adult epileptic ALG13KO mice, highlighting a stage-dependent role. SIGNIFICANCE: This study provides the first proteomic evidence of early postnatal suppression of the PI3K/AKT/mTOR pathway in a mouse model of ALG13-congenital disorder of glycosylation (ALG13-CDG). By integrating unbiased quantitative proteomics, targeted validation, and phenotyping, we identify the LAMC1-ITGA6-FAK axis as a novel upstream regulator mediating this suppression, linking a glycosylation defect directly to a key neurodevelopmental signaling hub. Importantly, our finding contrasts with reported mTOR hyperactivation in adult epileptic mice, revealing a critical, previously unrecognized stage-dependent duality of mTOR signaling in ALG13-CDG pathophysiology. This work not only advances the mechanistic understanding of neurodevelopmental deficits in CDG but also showcases the power of a focused, early time-point proteomic strategy to disentangle primary developmental pathophysiology from secondary disease states.

Keywords: ALG13; Brain development; Congenital glycosylation disorders; N-glycosylation; Proteomics; mTOR pathway

DOI: https://doi.org/10.1016/j.jprot.2026.105695

Mol Genet Metab. 2026 Jun 07. pii: S1096-7192(26)00467-1. [Epub ahead of print]148(4): 110184

Recurrent hemophagocytic lymphohistiocytosis in COG deficiency: a case series and systematic review of inflammatory manifestations.

Antoine de Laitre, Magalie Barth, François Labarthe, Marine Tardieu, Julien Lejeune, Violette Goetz.

BACKGROUND: Conserved oligomeric Golgi (COG) deficiencies are rare congenital disorders of glycosylation characterized by severe multisystem involvement. Recurrent inflammatory episodes have been reported but remain poorly understood and are likely underrecognized.
METHODS: We describe three patients with COG6 or COG7 deficiency presenting recurrent episodes of hemophagocytic lymphohistiocytosis (HLH). In parallel, we conducted a systematic review of the literature to assess the frequency and characteristics of inflammatory manifestations in COG deficiency.
RESULTS: All three patients experienced recurrent febrile episodes associated with biological features of HLH. In two cases, these episodes were followed by neurological deterioration and onset of epilepsy. Early or prophylactic corticosteroid therapy during febrile episodes appeared to mitigate both the severity and neurological impact of inflammatory flares. The literature review identified recurrent, unexplained, and poorly tolerated febrile episodes in approximately 40% of reported patients. Only one additional case of fully documented HLH was identified. However, multiple reports described partial or suggestive HLH features, supporting the hypothesis that hyperinflammatory manifestations are underdiagnosed in this population.
CONCLUSION: COG deficiencies, especially COG6 and COG7, may be complicated by recurrent and potentially severe hyperinflammatory episodes, including HLH, with significant neurological consequences. These findings suggest a link between glycosylation defects and immune dysregulation. Early recognition and preventive anti-inflammatory strategies are recommended.

Keywords: CDG syndrome; Golgi trafficking; Hemophagocytic lymphohistiocytosis; Immune dysregulation

DOI: https://doi.org/10.1016/j.ymgme.2026.110184

Pediatr Allergy Immunol. 2026 Jun;37(6): e70405

PGM3-SCID: Differential impact of glycosylation on lymphocyte lineage development and function.

John Cherneskie, Samuel Chiang, Nagako Akeno, Ian Shaw, Samuel Le, Cristina Cobb, Erika Owsley, Trong Le.

Keywords: NK‐cell function; PGM3 deficiency; SCID; T follicular helper cells; UDP‐GlcNAc; congenital disorder of glycosylation; newborn screening; skeletal dysplasia

DOI: https://doi.org/10.1111/pai.70405