Centralized Modularity of N-Linked Glycosylation Pathways in Mammalian Cells

TL;DR

This study reveals that N-linked glycosylation pathways in mammalian cells are highly modular, with a structure that allows for controlled glycan synthesis, providing insights for therapeutic glycoprotein engineering.

Contribution

It uncovers the modular organization of N-linked glycosylation pathways and how upstream control influences glycan production, a novel structural insight.

Findings

Glycosylation pathways are composed of cohesive modules.

Modules are controlled by upstream glycan synthesis pathways.

Cross-talk between modules is moderate and transcriptionally regulated.

Abstract

Glycosylation is a highly complex process to produce a diverse repertoire of cellular glycans that are attached to proteins and lipids. Glycans are involved in fundamental biological processes, including protein folding and clearance, cell proliferation and apoptosis, development, immune responses, and pathogenesis. One of the major types of glycans, N-linked glycans, is formed by sequential attachments of monosaccharides to proteins by a limited number of enzymes. Many of these enzymes can accept multiple N-linked glycans as substrates, thereby generating a large number of glycan intermediates and their intermingled pathways. Motivated by the quantitative methods developed in complex network research, we investigated the large-scale organization of such N-linked glycosylation pathways in mammalian cells. The N-linked glycosylation pathways are extremely modular, and are composed of cohesive topological modules that directly branch from a common upstream pathway of glycan synthesis. This unique structural property allows the glycan production between modules to be controlled by the upstream region. Although the enzymes act on multiple glycan substrates, indicating cross-talk between modules, the impact of the cross-talk on the module-specific enhancement of glycan synthesis may be confined within a moderate range by transcription-level control. The findings of the present study provide experimentally-testable predictions for glycosylation processes, and may be applicable to therapeutic glycoprotein engineering.