α2,3-Sialylation with Fucosylation Associated with More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease.

Dermatomyositis (DM) is a heterogeneous autoimmune disease associated with numerous myositis specific antibodies (MSAs) in which DM with anti-melanoma differentiation-associated gene 5-positive (MDA5 + DM) is a unique subtype of DM with higher risk of developing varying degrees of Interstitial lung disease (ILD). Glycosylation is a complex posttranslational modification of proteins associated with many autoimmune diseases. However, the association of total plasma N-glycome (TPNG) and DM, especially MDA5 + DM, is still unknown. TPNG of 94 DM patients and 168 controls were analyzed by mass spectrometry with in-house reliable quantitative method called Bionic Glycome method. Logistic regression with age and sex adjusted was used to reveal the aberrant glycosylation of DM and the association of TPNG and MDA5 + DM with or without rapidly progressive ILD (RPILD). The elastic net model was used to evaluate performance of glycans in distinguishing RPLID from non-RPILD, and survival analysis was analyzed with N-glycoslyation score by Kaplan-Meier survival analysis. It was found that the plasma protein N-glycome in DM showed higher fucosylation and bisection, lower sialylation (α2,3- not α2,6-linked) and galactosylation than controls. In MDA5 + DM, more severe disease condition was associated with decreased sialylation (specifically α2,3-sialylation with fucosylation) while accompanying elevated H6N5S3 and H5N4FSx, decreased galactosylation and increased fucosylation and the complexity of N-glycans. Moreover, glycosylation traits have better discrimination ability to distinguish RPILD from non-RPILD with AUC 0.922 than clinical features and is MDA5-independent. Survival advantage accrued to MDA5 + DM with lower N-glycosylation score (p = 3e-04). Our study reveals the aberrant glycosylation of DM for the first time and indicated that glycosylation is associated with disease severity caused by ILD in MDA5 + DM, which might be considered as the potential biomarker for early diagnosis of RPILD and survival evaluation of MDA5 + DM. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00096-z.

Generalized low levels of serum N-glycans associate with better health status.

Caloric restriction (CR) can prolong life and ameliorate age-related diseases; thus, its molecular basis might provide new insights for finding biomarker and intervention for aging and age-related disease. Glycosylation is an important post-translational modification, which can timely reflect the changes of intracellular state. Serum N-glycosylation was found changed with aging in humans and mice. CR is widely accepted as an effective anti-aging intervention in mice and could affect mouse serum fucosylated N-glycans. However, the effect of CR on the level of global N-glycans remains unknown. In order to explore whether CR affect the level of global N-glycans, we performed a comprehensive serum glycome profiling in mice of 30% calorie restriction group and ad libitum group at 7 time points across 60 weeks by MALDI-TOF-MS. At each time point, the majority of glycans, including galactosylated and high mannose glycans, showed a consistent low level in CR group. Interestingly, O-acetylated sialoglycans presented an upward change different from other derived traits, which is mainly reflected in two biantennary α2,6-linked sialoglycans (H5N4Ge2Ac1, H5N4Ge2Ac2). Liver transcriptome analysis further revealed a decreased transcriptional level of genes involved in N-glycan biosynthesis while increased level of acetyl-CoA production. This finding is consistent with changes in serum N-glycans and O-acetylated sialic acids. Therefore, we provided one possible molecular basis for the beneficial effect of CR from N-glycosylation perspective.