Protein O-mannosylation in the early secretory pathway

•O-Mannosylation initiates at the translocon complex in the endoplasmic reticulum (ER).•O-Man glycans can mark and exclude unfavorable folding intermediates (UPOM).•O-Mannosylation is an integral part of the interlinked ER protein homeostasis network.•New insights from high throughput MS-based glycoproteomics are discussed.

Protein O-mannosylation and N-glycosylation are essential post-translational modifications, which initiate in the endoplasmic reticulum (ER). In yeast, the two glycosylation machineries act at the Sec61 translocon complex where they can even compete for certain substrate proteins. N-linked glycans play a crucial role in the ER quality control of glycoproteins. In recent years, it became clear that in addition to its important functions for cell surface proteins, O-mannosylation impacts the ER protein homeostasis. These glycans can exclude unfavorable folding intermediates from futile folding attempts, increase the solubility of irreversibly misfolded proteins, and even mark them for degradation. O-Mannose glycoproteomics now captures the molecular complexity of this modification opening exciting opportunities to explore further roles of O-mannosylation in the early secretory pathway.

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