Group B Streptococcus GAPDH Is Released upon Cell Lysis, Associates with Bacterial Surface, and Induces Apoptosis in Murine Macrophages

Abstract

Glyceraldehyde 3-phosphate dehydrogenases (GAPDH) are cytoplasmic glycolytic enzymes that, despite lacking identifiable secretion signals, have been detected at the surface of several prokaryotic and eukaryotic organisms where they exhibit non-glycolytic functions including adhesion to host components. Group B Streptococcus (GBS) is a human commensal bacterium that has the capacity to cause life-threatening meningitis and septicemia in newborns. Electron microscopy and fluorescence-activated cell sorter (FACS) analysis demonstrated the surface localization of GAPDH in GBS. By addressing the question of GAPDH export to the cell surface of GBS strain NEM316 and isogenic mutant derivatives of our collection, we found that impaired GAPDH presence in the surface and supernatant of GBS was associated with a lower level of bacterial lysis. We also found that following GBS lysis, GAPDH can associate to the surface of many living bacteria. Finally, we provide evidence for a novel function of the secreted GAPDH as an inducer of apoptosis of murine macrophages.

Identification and Characterization of Porphyromonas gingivalis Client Proteins That Bind to Streptococcus oralis Glyceraldehyde-3-Phosphate Dehydrogenase

“…However, multiple functions have been reported recently for GAPDH, including roles in membrane fusion, microtubule binding, phosphotransferase activity, nuclear RNA export, DNA replication and repair, apoptosis, and viral pathogenesis (20,21). Our previous study demonstrated that the P. gingivalis FimA fimbria binding domain in S. oralis ATCC 9811 GAPDH was within amino acid residues 166 to 183, and that the peptide corresponding to this domain (DNFGVVEGLMTTIHAYTG) exhibited strong binding activity toward recombinant FimA fimbriae (rFimA) by BIAcore analysis (K A ϭ 4.51 ϫ 10 7 M Ϫ1 ) (22).…”

Excreted Cytoplasmic Proteins Contribute to Pathogenicity in Staphylococcus aureus

“…An explanation for the finding that GAPDH is toxic for MonoMac 6 but not for HaCaT cells could lie in an enhanced internalization (endocytosis-like?) of GAPDH, which might cause apoptosis, as reported for the Streptococcus pyogenes and S. aureus GAPDH proteins (10). However, this cytotoxic activity could contribute to the virulence of S. aureus, maybe not at the same high level as alpha-toxin but to a noticeable extent.…”

“…6A and B). For GAPDH of group B streptococci (GBS) and S. pyogenes, it has been previously described that they induce apoptosis in murine macrophages (10). How the two, seemingly harmless, glycolytic enzymes FbaA and GAPDH affect the viability of host cells is unclear.…”

“…It also stimulates B lymphocytes and induces early interleukin-10 (IL-10) production that facilitates host colonization (9). In group B streptococci (GBS) GAPDH acts as an inducer of apoptosis of murine macrophages (10). Moreover, in enterohemorrhagic and enteropathogenic Escherichia coli, GAPDH was exposed on the surface, where it binds to human plasminogen and fibrinogen, suggesting a role in pathogenesis (11).…”

Bovine Mastitis Caused By Streptococcus uberis: Virulence Factors and Biofilm

“…Madureira et al (2007) demonstrated that S. agalactiae GAPDH is a virulence-associated immunomodulatory protein [80]. Oliveira et al (2012) reported a new and different function of the secreted GAPDH as an inducer of apoptosis of murine macrophages [81]. As the enzyme has also different functions to the original, it has been called "moonlighting proteins" [82].…”