Role for α- l -fucosidase in the control of Helicobacter pylori -infected gastric cancer cells

Abstract

Infecting about one-half of the global human population, Helicobacter pylori is well established as the primary cause of gastritis, duodenal ulcer, and gastric cancer. Currently there is no clear information regarding if and how host cells interact with H. pylori, and if such interactions are dependent on the type of gastric disease. Using fluorescently labeled fucose-containing glycoconjugates, we provide evidence observing both the uptake of L-fucose from gastric cancer cells to H. pylori and that human ␣-L-fucosidase 2 (FUCA2) is secreted only under coculture conditions (i.e., host cells infected with H. pylori). Upon depletion of FUCA2 by RNA interference and detection of translocated CagA (a virulence factor of H. pylori) in host cells, FUCA2 was found to be essential for H. pylori adhesion, in particular to the gastric cancer-and duodenal ulcer-specific strains. Additionally FUCA2 was shown to significantly enhance the expression of Lewis x antigen in H. pylori, which is critical for bacterial cell adhesion in the pathogenesis and defense strategy to escape host surveillance. These findings not only demonstrate an important connection between FUCA2 and the adhesion, growth, and pathogenicity of H. pylori, but also support the idea that FUCA2 is a potential target for clinical diagnosis and therapeutic intervention of H. pylori-related diseases.

Phenotypic and Genotypic Evidence for l -Fucose Utilization by Campylobacter jejuni

“…Although no fucosidase homolog was identified in the C. jejuni genome, it is plausible that intestinal commensals produce the enzyme to cleave the fucose from the host glycoconjugate. Alternatively, Helicobacter pylori, a close relative of Campylobacter, has been shown to direct host cells to produce ␣-L-fucosidase, freeing the fucose from the glycoconjugate directly (30). Secreted mucin has been suggested to increase the viability of C. jejuni (1), indicating that C. jejuni is capable of directly degrading or inducing the host to degrade mucin into components that support growth.…”

Role of Energy Sensor TlpD of Helicobacter pylori in Gerbil Colonization and Genome Analyses after Adaptation in the Gerbil

“…One genetic change in the coding region of an ␣-1,2-fucosyltransferase gene, futC (HP0093), which is involved in Le y surface glycosylation (64,76) (Table 6), corresponded to a switched-on Le y phenotype. In humans and in gerbils, the surface expression of Lewis y in the stomach increases during chronic H. pylori infection and is induced by proinflammatory effects (64,77), and Le y fucosyl residues can be taken up and utilized by H. pylori (77). The active function of HP0093 might be related to changed adherence to gastric tissue, to the metabolic utilization of host fucose moieties (77), or to improved immune evasion by surface mimicry.…”

Structure and Substrate Specificity of a Eukaryotic Fucosidase from Fusarium graminearum

“…FUCA1 is a lysosomal enzyme whose deficiency causes fucosidosis, a disease characterized by progressive mental and motor deterioration (2). FUCA2 is a secreted enzyme and is essential for Helicobacter pylori adhesion during infection of gastric cancer cells (34). In contrast, GH29 enzyme Bt2970 from the enteric bacterium Bacteroides thetaiotaomicron is much more active on pNP-Fuc than on natural ␣-fucosyl linkages (22).…”

“…Human GH29 fucosidases, FUCA1 and FUCA2, are both active on ␣1,2/3/4/6-linked fucosyl substrates as well as pNP-Fuc (20,21,31,34). FUCA1 is a lysosomal enzyme whose deficiency causes fucosidosis, a disease characterized by progressive mental and motor deterioration (2).…”