O-GLYCOSYLATION PATTERNS IN POST-VIRAL FATIGUE SYNDROME: SIALIC ACID-PRESERVING CHEMICAL RELEASE, 2025, de Otazo Hernández

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O-GLYCOSYLATION PATTERNS IN POST-VIRAL FATIGUE SYNDROME: SIALIC ACID-PRESERVING CHEMICAL RELEASE

Daniel García de Otazo Hernándeza,b, Gianluigi Sabatinoa, Eva Untersmayr b, Selina Kepplerc, Davide Reta,b

a Research Unit Macromolecular Chemistry, Institute of Applied Synthetic Chemistry, TU Wien, 1060 Vienna, Austria daniel.garcia@tuwien.ac.at

b Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria c Division of rheumatology and Immunology Medical University of Graz, 8010 Graz, Austria

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex inflammatory condition characterized by chronic fatigue, post-exertional malaise, and immune dysregulation whose underlying mechanisms remain poorly understood. Glycosylation, the process of attaching glycans to proteins and lipids, plays a crucial role in immune cell communication and inflammation [1]. As sialic acid has great importance in autoimmune and inflammatory diseases, the focus was directed towards a controlled release and labelling reaction with all conditions avoiding acidic hydrolysis of sialic acid [Figure 1.].

O-glycan from blood sera and purified antibodies where methyl amidated to stabilize sialic acid [2]. The release reaction proceeds via non-reductive β-elimination and subsequent labelling with a fluorescent compound in conditions able to conserve sialic acid in antennary position. The O-glycan profiles are analyzed by HPLC with fluorescence and MALDI mass spectrometry.

O-glycosylation profiles with intact sialylation of ME/CFS patients and healthy controls reveal an altered O-Glycan pattern which may contribute to the chronic inflammatory state observed in ME/CFS.

Figure 1. Graphical abstract.

O-Glycans from blood serum and antibodies were analyzed from patients and healthy controls using a novel release and labelling method. Image created with BioRender.

References:

1. Rohrhofer, J., et al., Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Clinical Medicine, 2024. 13(1): p. 275.

2. Ret, D., et al., DMTMM-mediated methylamidation for MALDI mass spectrometry analysis of N-glycans with structurally conserved sialic acid residues in biological fluids "via direttissima". Talanta, 2022. 242: p. 123326.

The 22nd European Carbohydrate Symposium, 6-10 July 2025 GDAŃSK, POLAND
 
I've shared this paper before, but one possible reason for changes in glycosylation is endoplasmic reticulum stress. ER stress causes a homeostatic response called the 'unfolded protein response' which has many effects, including, the paper says, changing the way glycans get added to proteins.

And when those glyosylated proteins are expelled from the cell, they can act as a signal of cellular stress or infection.

Protein Glycosylation Patterns Shaped By the IRE1-XBP1s Arm of the Unfolded Protein Response
Kenny Chen 1 , Matthew D Shoulders 1 2
Affiliations

Abstract
The unfolded protein response (UPR) is a sensing and signaling pathway that surveys the endoplasmic reticulum (ER) for protein folding challenges and responds whenever issues are detected. UPR activation leads to upregulation of secretory pathway chaperones and quality control factors, as well as reduces the nascent protein load on the ER, thereby restoring and maintaining proteostasis. This paradigm-defining view of the role of the UPR is accurate, but it elides additional key functions of the UPR in cell biology. In particular, recent work has revealed that the UPR can shape the structure and function of N- and O-glycans installed on ER client proteins. This crosstalk between the UPR's response to protein misfolding and the regulation of glycosylation remains insufficiently understood. Still, emerging evidence makes it clear that the UPR, and particularly the IRE1-XBP1s arm of the UPR, may be a central regulator of protein glycosylation with important biological consequences. In this review, we discuss the crosstalk between proteostasis, the UPR, and glycosylation, present progress towards understanding biological functions of this crosstalk, and examine potential roles in diseases such as cancer.


This all ties back to Hwang's study where he found signs of endoplasmic reticulum stress in mecfs,that was causing wasf3 to get into mitochondria. If there is chronic ER stress it could be having effects on glycosylation too.
 
I agree with @Murph but just to say that N-Linked glycosylation can also lead to ER Stress (and N-Linked glycosylation has a direct effect on ER Stress as opposed to O-Linked glycosylation).

I wonder if these researchers looked at N-Linked glycosylation as well or if they are planning to. I will try to contact them to know more. Thanks for the tag @wigglethemouse
 
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