Role of TMEM230 in the Aberrant Glycosylation in Human Autoimmunity and Cancer

Alterations in glycoconjugate profiles are thought to promote changes in cell-to-cell and cell-to-intracellular and extracellular scaffold interactions in human disease. The nearly unlimited number of “glycoforms” that may exist in nature are difficult to study due to glycosylation and glycoconjugate modifications being associated with non-genome coded posttranscription and post-translation processes. Specific products generated by glycosylation are dependent on concentration and sub-cellular locations of glycan synthesis and processing enzymes. An indirect “high-throughput” approach to study glycosylation is to characterize glycan processing enzymes (hydrolases and transferases) by single cell sequencing of all cell types in tissue of human diseases. We previously identified TMEM230 as an endoplasmic reticulum (ER) associated protein that regulates NOTCH glycoprotein receptor and ligand signaling in zebrafish blood vessel formation and destructive remodeling capacities of diverse cell types including fibroblast, phagocytic and immune system cells in patients with cancer or granulomatous systemic vasculitis autoimmune disorder. NOTCH signaling represents a paradigm in glycan mediated signal transduction and supports the role of TMEM230 in glycan modifications. The ER initiates the earliest steps of glycoconjugate synthesis, sorting, and trafficking. As blood vessel and tissue remodeling, and Notch signaling are hallmarks of autoimmune disorders, we investigated whether aberrant TMEM230 expression was also associated with changes in expression of glycan processing enzymes in patients with rheumatoid arthritis (RA). In this current study, single cell sequencing analysis supported that TMEM230 expression was downregulated in all cell types associated with synovial tissue of RA patients while glycan processing enzymes were predominantly upregulated. In contrast, TMEM230 was upregulated in patients with high-grade compared to low-grade gliomas as it was N-linked glycosylation (GlcNAc), and glycoprotein and glycosaminoglycan expression. Our collective results support that TMEM230 regulates glycan/glycoconjugate processing enzymes in RA and the expression of protein glycoconjugate in aggressive gliomas. TMEM230 may therefore be a therapeutic target and marker for clinical treatment for glycosylation induced human autoimmunity disorders or cancer.