Moonlighting glycolytic protein glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH): an evolutionarily conserved plasminogen receptor on mammalian cells

Abstract

Prokaryotic pathogens establish infection in mammals by capturing the proteolytic enzyme plasminogen (Plg) onto their surface to digest host extracellular matrix (ECM). One of the bacterial surface Plg receptors is the multifunctional glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In a defensive response, the host mounts an inflammatory response, which involves infiltration of leukocytes to sites of inflammation. This requires macrophage exit from the blood and migration across basement membranes, a phenomenon dependent on proteolytic remodeling of the ECM utilizing Plg. The ability of Plg to facilitate inflammatory cell recruitment critically depends on receptors on the surface of phagocyte cells. Utilizing a combination of biochemical, cellular, knockdown, and approaches, we demonstrated that upon inflammation, macrophages recruit GAPDH onto their surface to carry out the same task of capturing Plg to digest ECM to aid rapid phagocyte migration and combat the invading pathogens. We propose that GAPDH is an ancient, evolutionarily conserved receptor that plays a key role in the Plg-dependent regulation of macrophage recruitment in the inflammatory response to microbial aggression, thus pitting prokaryotic GAPDH against mammalian GAPDH, with both involved in a conserved role of Plg activation on the surface of their respective cells, to conflicting ends.-Chauhan, A. S., Kumar, M., Chaudhary, S., Patidar, A., Dhiman, A., Sheokand, N., Malhotra, H., Raje, C. I., Raje, M. Moonlighting glycolytic protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH): an evolutionarily conserved plasminogen receptor on mammalian cells.

Trafficking of a multifunctional protein by endosomal microautophagy: linking two independent unconventional secretory pathways

“…Real‐time quantitative PCR was performed using the ABI Fast Real‐Time PCR System (Thermo Fisher Scientific) using the Fast SYBR Green Master Mix (4385612; Thermo Fisher Scientific), according to the manufacturer's instructions. The data were normalized with actin as an internal control and analyzed using the 2 −ΔΔ Ct method, as previously described (33).…”

HtrA of Borrelia burgdorferi Leads to Decreased Swarm Motility and Decreased Production of Pyruvate

“…Enzymes involved in metabolic regulation can localize to the bacterial surface and have additional biological properties in bacterial virulence ( 40 ). Moonlighting GAPDH is one such surface-located ligand for plasminogen ( 41 ). We presented evidence for possible moonlighting by the GAPDH of B. burgdorferi in addition to its traditional enzymatic role in the glycolytic pathway ( 42 , 43 ).…”

Why Do Intravascular Schistosomes Coat Themselves in Glycolytic Enzymes?

“…Currently, Gram‐positive organisms such as streptococci and staphylococci and the cell wall‐deficient mycoplasmas are said to have most of the enzymes of the glycolytic pathway on their cell surfaces, and glycolytic enzymes have been detected at the surface of parasitic protists like Entamoeba histolytica and Plasmodium spp . Indeed, some yeast cells and mammalian cells are also reported to express some glycolytic enzymes at their surfaces …”