Paucimannosylation

Etymology

The term "paucimannose" was introduced in the early 1990s glycobiology literature, combining the Latin prefix "pauci" (few or small) with "mannose" to describe glycans that terminate in mannose. The phrases protein paucimannosylation and paucimannosidic proteins refer to glycoproteins carrying such modifications. The oligosaccharides themselves are called paucimannosidic, low mannose, or truncated glycans. A shorthand nomenclature, such as M3F for Man3GlcNAc2Fuc1, has been proposed for individual structures.

Tissue expression and (sub-) cellular localisation

Paucimannosylation is constitutively and broadly expressed across tissues in insects, nematodes, and plants under normal physiology. In insects such as Drosophila melanogaster, paucimannosidic glycans dominate the N-glycome; in the western honeybee Apis mellifera, they modify venom proteins like hyaluronidase and phospholipase. Insect cell lines used for recombinant expression of mammalian glycoproteins (e.g., mouse interferon-β, human IgG1, calf alkaline phosphatase) produce paucimannosidic glycans. In nematodes, including Caenorhabditis elegans, Pristionchus pacificus, and parasitic species such as Haemonchus contortus, Ascaris suum, Heligmosomoides polygyrus, and Trichuris suis, paucimannosidic glycans are documented.

Most studied plants express paucimannosidic N-glycoproteins abundantly in vacuoles, as seen in legume seeds of Lotus japonicus and rice seeds and leaves of Oryza sativa. Plant-specific structures modified with xylose and fucose occur across Streptophyta, Chlorophyta, and diatoms like Phaeodactylum tricornutum. In vertebrates, paucimannosylation is more tissue- and context-restricted, appearing in pathophysiological conditions such as cancer, infection, inflammation, and stemness.

Biosynthesis of paucimannosidic N-glycoproteins

The biosynthesis of paucimannosidic proteins involves a limited set of glycoenzymes, including beta-N-acetylhexosaminidases (Hex) and alpha-mannosidases, acting through GnT-I-dependent and -independent truncation pathways. In Drosophila melanogaster, the fused lobe (fdl) gene encoding fused ß-lobe (FDL), an orthologue of human Hex, is expressed in vesicles and plasma membrane and is linked to paucimannosidic protein production. In Caenorhabditis elegans, a GnT-I-dependent route produces GlcNAc-capped intermediates, which are then processed by two Hex isoenzymes (HEX-2 and HEX-3) to generate unsubstituted paucimannosidic glycans.

Additional processing by α-Man II and α1,6- and α1,3-fucosyltransferases contributes to structural diversity. A GnT-I-independent α1,6-fucosyltransferase also operates in C. elegans, suggesting both pathways may contribute. The biosynthetic processes for unusual non-sugar and core-modified paucimannosidic N-glycans in C. elegans remain to be elucidated.

Functions of protein paucimannosylation

In vertebrates, paucimannosylation is implicated in pathophysiological processes including inflammation, pathogen infection, cancer, stem cell development, and normal homeostasis. Elevated paucimannosidic proteins have been observed in Mycobacterium tuberculosis-infected macrophages, during preeclampsia, on Tamm-Horsfall proteins in urinary tract infections, and in sputum from cystic fibrosis and airway infection patients. Paucimannosylation is prominent in human neutrophils, monocytes, and macrophages. Elevated signatures are associated with brain, breast, blood, melanoma, non-melanoma, liver, ovarian, and prostate cancers, with enriched glycoepitopes in tumours compared to adjacent non-tumour tissues.

Paucimannosylation also occurs in embryonic and neuronal stem cells. Deficiency of hexosaminidases leads to Tay-Sachs and Sandhoff diseases. Endogenous binding partners include macrophage mannose receptor (CD206) and dectin-2; exogenous binders include Escherichia coli FimH and Pseudomonas aeruginosa PA-IIL.

Did You Know?

• Additional modifications with fucose, xylose, and/or galactose are common in mammals, plants, and invertebrates, respectively.
• Paucimannosidic glycans expressed by insects and nematodes are particularly rich in structural diversity.