A bacterial ABC transporter enables import of mammalian host glycosaminoglycans

Abstract

Glycosaminoglycans (GAGs), such as hyaluronan, chondroitin sulfate, and heparin, constitute mammalian extracellular matrices. The uronate and amino sugar residues in hyaluronan and chondroitin sulfate are linked by 1,3-glycoside bond, while heparin contains 1,4-glycoside bond. Some bacteria target GAGs as means of establishing colonization and/or infection, and bacterial degradation mechanisms of GAGs have been well characterized. However, little is known about the bacterial import of GAGs. Here, we show a GAG import system, comprised of a solute-binding protein (Smon0123)-dependent ATP-binding cassette (ABC) transporter, in the pathogenic Streptobacillus moniliformis. A genetic cluster responsible for depolymerization, degradation, and metabolism of GAGs as well as the ABC transporter system was found in the S. moniliformis genome. This bacterium degraded hyaluronan and chondroitin sulfate with an expression of the genetic cluster, while heparin repressed the bacterial growth. The purified recombinant Smon0123 exhibited an affinity with disaccharides generated from hyaluronan and chondroitin sulfate. X-ray crystallography indicated binding mode of Smon0123 to GAG disaccharides. The purified recombinant ABC transporter as a tetramer (Smon0121-Smon0122/Smon0120-Smon0120) reconstructed in liposomes enhanced its ATPase activity in the presence of Smon0123 and GAG disaccharides. This is the first report that has molecularly depicted a bacterial import system of both sulfated and non-sulfated GAGs.

Glycan‐metabolizing enzymes in microbe–host interactions: the Streptococcus pneumoniae paradigm

“…Many of the enzymes and transporters covered in this review are considered part of the 'core' genome of S. pneumoniae [15]; therefore, they are clearly important to the lifestyle of this bacterium. Analogous proteins and pathways are also present in a range of other bacterial commensals and pathogens, such as O-glycan degradation by Enterococcus faecalis [198] and Bifidobacterium longum [199], N-glycan degradation by Bacteroides fragilis [6], Clostridium perfringens [66] and Salmonella typhimurium [3], and GAG processing by other streptococci [170] and Streptobacillus moniliformis [200]; however, in many of these cases, the role of these pathways in virulence has not been investigated. Therefore, the pneumococcal pathways and extensive virulence associations presented here act as an invaluable model for ongoing research into the role of glycan metabolism in the relationship between the host and other microbes.…”

Alternative substrate-bound conformation of bacterial solute-binding protein involved in the import of mammalian host glycosaminoglycans

“…1C ), as well as hyaluronan and chondroitin sulfate C 8 . We have previously demonstrated that the ABC transporter incorporated GAG disaccharides derived from hyaluronan (ΔHA, unsaturated hyaluronan disaccharide) and chondroitin sulfate (CΔ0S, CΔ4S, and CΔ6S) 8 . This substrate specificity of the ABC transporter suggests that S. moniliformis degrades other chondroitin sulfates that have two sulfate groups in their constitutional units, such as chondroitin sulfates D and E. The plate assay using abundant GAGs was not attempted because chondroitin sulfates D and E are expensive.…”

“…In the plate, clear halo zones were observed around S. moniliformis cells, indicating that this bacterium could degrade chondroitin sulfate A (Fig. 1C ), as well as hyaluronan and chondroitin sulfate C 8 . We have previously demonstrated that the ABC transporter incorporated GAG disaccharides derived from hyaluronan (ΔHA, unsaturated hyaluronan disaccharide) and chondroitin sulfate (CΔ0S, CΔ4S, and CΔ6S) 8 .…”

“…The genes encoding these enzymes that are essential for depolymerization, degradation, and metabolism of GAGs assemble a cluster in the bacterial genome. We have recently identified a solute-binding protein-dependent ATP-binding cassette (ABC) transporter to be the first bacterial import system of both sulfated and non-sulfated GAG disaccharides in pathogenic Streptobacillus moniliformis 8 . S. moniliformis , a causative organism of rat bite fever, is characterized by relapsing fever, rash, and migratory polyarthralgias 9 .…”

Research on the roles of genes coding ATP‐binding cassette transporters in Porphyromonas gingivalis pathogenicity

“…[18][19][20] Eukaryotic ABC transporters play important roles in the import of essential nutrients, the export of signaling molecules and toxins, and multidrug resistance in cancer cells. 25 Moreover, ABC transporters participated in the bacterial uptake of different nutrients, including Fe 2+ , amino acids, vitamins, and oligopeptides, thus contributing to bacteria survival in the host microenvironment. 22,23 ABC transporters were also shown to be involved in multiple colonization processes, including heme uptake and use, formation and morphology of biomembranes, bacterial adhesion and colonization, and interaction between bacteria.…”