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  • Review Article
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Protein glycosylation in bacterial mucosal pathogens

Abstract

In eukaryotes, glycosylated proteins are ubiquitous components of extracellular matrices and cellular surfaces. Their oligosaccharide moieties are implicated in a wide range of cell?cell and cell?matrix recognition events that are required for biological processes ranging from immune recognition to cancer development. Glycosylation was previously considered to be restricted to eukaryotes; however, through advances in analytical methods and genome sequencing, there have been increasing reports of both O-linked and N-linked protein glycosylation pathways in bacteria, particularly amongst mucosal-associated pathogens. Studying glycosylation in relatively less-complicated bacterial systems provides the opportunity to elucidate and exploit glycoprotein biosynthetic pathways. We will review the genetic organization, glycan structures and function of glycosylation systems in mucosal bacterial pathogens, and speculate on how this knowledge may help us to understand glycosylation processes in more complex eukaryotic systems and how it can be used for glycoengineering.

Key Points

  • It is now apparent that organisms from all three domains of life are capable of modifying their proteins through glycosylation.

  • Similar processes of glycoconjugate biosynthesis are conserved among all three domains by segregating key steps of the pathway with membranes, by the use of nucleotide-activated and/or lipid-linked intermediates, and by transfer of sugars to the same amino acid sequons.

  • Among Bacteria, mucosal pathogens have a particular propensity to glycosylate surface structures.

  • Mucosal pathogens frequently share similar sugar biosynthetic genes, resulting in similar glycans such as bacillosamine- and pseudaminic acid-like structures.

  • Campylobacter jejuni is unique among Bacteria as it has well-characterized O- and N-linked glycosylation systems.

  • The recent demonstration of the transfer of the Campylobacter N-linked glycosylation pathway into Escherichia coli opens up the possibility of producing recombinant glycoproteins. Together with the detailed characterization of several bacterial glycosylation pathways, the opportunity to engineer countless permutations of novel glycoproteins in a simple E. coli host is now possible.

  • Further characterization of the Campylobacter O- and N-linked glycosylation systems and other bacterial systems will provide useful models to study more complex eukaryotic protein glycosylation pathways.

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Figure 1: Space-filling models of the C. jejuni glycans from the O- and N-linked protein glycosylation systems.
Figure 2: Model for the biosynthesis of N- and O-linked glycoproteins in eukaryotes (a,b) in comparison to bacteria (c,d).
Figure 3: Gene schematic comparing bacterial N-linked protein glycosylation loci.

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Acknowledgements

We thank S. Logan for the critical reading of this review, J.-R. Brisson, N. M. Young and N. Khieu for constructing the space-filling models and M. Aebi for reviewing the manuscript and providing information prior to publication. We also thank R. Mandrell and W. Miller for providing genomic data for the Campylobacter species described in this review and for assembling online supplementary information S1 (Table). We gratefully acknowledge the NRC Genomics and Health Initiative for providing funding to C.M.S and the Leverhulme Trust and BBSRC for funding to B.W.W.

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DATABASES

Entrez

Campylobacter coli

C. jejuni NCTC 11168

C. jejuni RM1221

Campylobacter lari RM2100

Campylobacter upsaliensis RM3195

Cj1305c

Cj1306c

Cj1310c

Cj1318

Cj1333

Cj1334

Cj1335

Cj1336

Cj1337

Cj1340

Cj1341

Cj1342c

galE

Helicobacter pylori

Neisseria gonorrhoeae

Neisseria meningitidis

neuA2

neuA3

neuB2

neuB3

neuC2

Pseudomonas syringae

Wolinella succinogenes

SwissProt

FlaA

FlaB

PglA

PglB

PglC

PglD

PglE

PglF

PilO

STT3

TibA

WlaB

FURTHER INFORMATION

CampyDB

Desulfovibrio desulfuricans genome

Christine M. Szymanski's laboratory

Brendan W. Wren's laboratory

Glossary

FLAGELLIN

The structural protein of which the bacterial flagellum is constructed.

LIPOPOLYSACCHARIDE

(LPS). An important amphiphilic molecule integrated in and extending outward from the outer membrane of the Gram-negative bacterial cell wall; structurally composed of hydrophobic Lipid A (responsible for endotoxin activity), core polysaccharide and hydrophilic O-antigen polysaccharide side chains.

LIPOOLIGOSACCHARIDE

(LOS). Similar to LPS but lacking the O-antigen polysaccharide side chain repeats.

CAPILLARY ELECTROPHORESIS COUPLED TO ELECTROSPRAY MASS SPECTROMETRY

(CE-ESMS). A coupled system where complex mixtures are first separated by capillary electrophoresis before being introduced into the mass spectrometer using electrospray ionization.

S-LAYER PROTEIN

Surface (S) layers are composed of a crystalline array of high-molecular-weight protein or glycoprotein subunits and form a matrix surrounding some bacterial cells.

CAPSULAR POLYSACCHARIDE

(CPS). Also sometimes referred to as K-antigen, capsules are composed of polysaccharide repeats that surround some bacterial cells and are anchored in the membrane by a terminal lipid moiety.

O-ANTIGEN

A polysaccharide antigen extending from the outer membrane of some Gram-negative bacterial cell walls that is a part of the LPS; this repeat is also the serodeterminant for the classical heat-stable O-typing scheme.

FRAMESHIFT MUTATION

A mutation arising from the loss or gain of a base or DNA segment leading to a change in the codon reading frame and thus a change in the amino acids incorporated into the protein.

PHASE VARIATION

Variable expression of a structure that is governed by random frameshift mutations within genes responsible for the biosynthesis of the structure or through changes in the regulation of structure synthesis.

HIGH-RESOLUTION MAGIC-ANGLE SPINNING NMR

(HR-MAS NMR). An adaptation of solid-state NMR where samples are spun rapidly around an axis inclined at an angle of 54.7°, the 'magic angle', with the direction of the magnetic field.

LIPOCHITOOLIGOSACCHARIDE

Plant bacteria signalling molecules, also known as Nod factors, that consist of a backbone of 2?6 β-(1→4)-linked GlcNAc residues with an amide-bound fatty acyl residue (saturated or unsaturated) on the non-reducing terminal GlcN residue. This basic structure has variations that are dependent on each strain or species and determine the host specificity.

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Szymanski, C., Wren, B. Protein glycosylation in bacterial mucosal pathogens. Nat Rev Microbiol 3, 225–237 (2005). https://doi.org/10.1038/nrmicro1100

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